Immunopathology

All rights Reserved © 2017 Prof.Dr. Khalil Hassan Zenad Aljeboori
Immunopathology For Postgraduate
Students In The Colleges;
Medicine ,Dentistry And Vet. Medicine
Prof.Dr.
Khalil Hassan Zenad Aljeboori

-Chapter one-
Immune regulation:
All the diseases are regulatied by immune response, this
regulation is important so disorder of the regulation
resulted in autoimmune diseases or immuno deficiency.
1- Normal regulation:
Factors regulating IR are complex include:
(a) Ag availability.
(b) Specific suppression by T cells.
(C) The influence of antiidiotype Abs.
)d) balance of cytokines..

Ag availability:
Ag triggers IR normally, the concentration of Ag fall as it is
metabolized or removed by Immune process. The basic stimulus for
the IR become weaker, triggering only clones that carry high affinity
receptors (i.e those are keenest to bind A g). since plasma cells are
short lived the rate at which Ag triggers B cells is probably an
important rate limiting step in Ab production.
Anti idiotype:
The structure of Ag binding site is unique to each Ab, and is called
idiotype and it is itself Agic. Some antiidiotype Ab is produced
naturally in the course of normal IR such Ab is by definition an
autoantibody. There is evidence that such antiidiotype Ab involved in
the normal regulation of IR. Especially controlling the production of
outantibodies.

2- Altered regulation:
The factor which regulate the IR can be manipulated
experimentally. Appropriate adjustments in the dose,
route or timing of first exposure to an Ag may prevent
the IR from occurring. This state of unresponsive is
know as tolerance. The mechanism involved are not
clear and induction of tolerance remains a theoretical
therapeutic goal.

Failure of self tolerance:
1- lead to autoimmune diseases but the precise stimulus which trigger the
production of outsensitized lymphocytes and autoantibodies is un known, there
are several ways in which auto reactive T cell may be activated and in turn
activate and help autoreactive B cells. Self Ag may become altered by a virus or a
drug cross react with extrinsic Ags or Abs to them.
The resultant autoantibodies may cause damage to the organ in which AutoAg
are found, Auto Abs which cause damage are known as primary Abs while those
produced as the result of tissue damage with (liberation of tissue Ag) are known
as secondary Abs. Evidence suggests that Abs are probably more important than
cells in inducing organ specific damage. Relatives of patients with autoimmune
disorders are also in risk of developing organ specific autoimmune diseases. The
member of such families may have serum auto Abs without overt disease.
It is possible that this familial trait is linked to the inheritance of excessively active
T. helper cells or poor suppression by T cells. Further more there is on association
between some autoimmune diseases and the particular HLA haplotype (HLA – A1,
B8, DR3). Which may reflect genetic susceptibility to autoimmune diseases .

-Chapter two-
Complements:
Complement system consists of series of serum proteins which are
activated in turn. The complement components normally exists in inactive
precursors and once activated the complement components act as
enzymes which cleave several molecules of the next component in the
sequence (rather like clotting cascade.
Each precursor cleaved into two or more fragments:
1 -The major fragment (designated b):
Has two biologically active sites
i.for bindings to cell membrane or to triggering , complex and the other.
ii- for enzymatic cleavage of the next component of complement..
Control of the sequence: involves spontaneous decay of any exposed
attachments sites and specific inactivation by complement inhibitors.
2- Minor fragments (designated a):
Generatedby cleavage of complement have important
biological properties in the fluid phase, such as chemotactic activity.
(activated component) e.g. : C1=C1-

The major purpose of complement pathway:
Is to provide a means of removing or destroying Ag regardless of whether or
not has become coated with Ab.
 The lysis of whole invading microorganisms is a dramatic example of the
complement activity of the compete sequence of complement activation.
 Opsonization of microorganisms and immune complexes, microorganisms
coated (i.e opsonized) with immunoglobulin and or complement and or
complement are more, easily, recognized by macrophages and bound and
phagocytosed by macrophages through, IgG-Fc and C3b receptors.
Similarly immune complexes are opsonized by their activation of the
classical pathway. Individuals who lack one of classical pathway suffer from
immune complex diseases. Soluble complexes are transported in
circulation from inflammatory sites by erythrocytes bearing CR1 which
bind to activated C3 (C3b) in immune complex. Once in spleen and liver
these complexes are removed, from red cells and then recycled.

Minor complement fragment are generated at every step of cascade
and contribute to the inflammatory response. Some increase vascular
permeability (C3a) while others attract neutrophils and macrophages for
subsequent opsonization and phagocytosis (C5a). C5a not only
promotes leukocyosis in the bone marrow but mobilizes and attract
neutrophils to inflammatory sites where it increases there adhesiveness,
it also up regulate complement receptor CR1 and CR3 on neutrophils
and macrophages to maximize phagocytosis.
Complement activation:
Occurs in two phases, activation of C3 component, followed by
activation of attack or lytic sequence. The critical step is the cleavage C3
by complement derived enzymes termed C3 convertase The major
fragment (C3b) of activated C3 mediates a number of vital biological
activities.

The cleavage of C3 is achieved by
two routes:
The classical and alternate pathways, both of which
can generate C3 convertase but in response to
different stimuli.

1- The Classical Pathway:
Was the first to be described and it is activated by number of substances, the widely
recognized being Ag- Ab complexes where the Ab is either IgM or IgG.
The reaction of IgM or IgG with its Ag cause conformational change in
the FC region of Ab to reveal a binding site for the first component in the classical pathway
(C1q), C1q is a collagen like protein composed of six units resemble a bunch of tulips when
seen under electron microscope. C1q reacts with Fc via globular head but attachment by two
critically spaced biding sites is needed for activation.
The Fc region is of pentameric Igm are so spaced that one IgM molecules
can activate C1q. in contrast IgG relatively inefficient because the chance of two randomly sited
IgG molecules being the critical distance apart to activate C1q is relatively low.
IgA, IgD and IgE do not activate the classical pathway.
Once C1q activated, C1r and C1s are sequentially bound to genetate, enzyme activity ( C1
estrase) for C4 and C2 splitting of both molecules into a and b fragments, the complex C4b2b
is the classical pathway C3 convertase.
Other fragments released are C4a, C2a and a kinin like peptide released from C2. C4b2b cleave
C3 into two fragments, one (C3a) possessing anaphylotoxic and chemotactic activity and one
which binds to inintiating complex and promote many of biological properties of complement,
the (C4b2b3b)complex so generated is an enzyme. C5 convertase which initiates the final lytic
pathway (the attack sequence).

2- The Alternate Pathway:
Was originally described in 1945 and accepted until the late 1960. It is phylogenitically
older than classical pathway. It is relatively inefficient in the tissue and high
concentrations of the various component are required the central reaction in this
pathway as in the classical pathway, is the activation of C3, the alternate pathway
however generate a C3 convertase without need for Ab, C1 , C4, C2 instead, the most
important activators are bacterial cell and endotoxin.
The initial cleavage of C3 in the alternate pathway happens continuously and
spontaneously, generating a low level of C3b . C3b is an unstable substance and if a
suitable receptor surface is not found, then the attachment site in C3b decays and the
molecules become inactive, If however an acceptor surface is nearby the C3b
molecules can bind and remain active. C3b is then able to use factors D and B of
alternate pathway to product the active enzyme C3bBb. The latter substance has two
properties, it can breakdown more C3 providing still more C3b, this is known as the
positive feedback loop of alternate pathway, alternatively, C3bBb become stabilized in
the presence of properdin.
To form the C5 convertase of the alternate pathway:
There are thus two way of producing C5 convertase. In the classical pathway it is made
up of C3b, C4b, and C2b, while in the alternate pathway it is produced by C3bBb and
properdin.

Final lytic pathway:
(attack sequence) of complement involves the sequential attachment of
component C5, C6,C7.C8 and C9 and result in lysis of target cell. The
target cell may be a red cells (commonly used in laboratories to
demonstrate complement), an invading organism or a virally infected
cell. The lytic pathway complex binds to the cell membrane and a
transmembrane channel is formed. This can be seen by electron
microscope as hollow thin walled cylinder through which the salts and
water may flow. This process lead up uptake of water by a cell, swelling
and destruction.
During the final lytic pathway complement component fragment are
broken off. C5a and the activated complex C567 are potent mediators
of inflammation. C5a and along with C3a, is anaphylotoxin that is it
cause histamine release from mast cells with a resulting increase in
vascular permeability. C5a also has the property of being able to attract
neutrophils to the site of complement activation (i.e chemotactic).

The control:
The control of any cascade sequence is extremely important particularly
when it result in the production of potentially self damaging mediators
of inflammation. The complement pathway is controlled by three
mechanisms:
1.A number of activated component are inherently unstable. If the
next protein in the pathway is not immediately available, the
active substance decays.
2.There are also a number of specific inhibitors for e.g: C1 estrase
inhibitors factor I, factor H.
3.There are on cell membrane , proteins that increase the rate of
breakdown of activated complement component . These
mechanism ensure that the potentially harmful effects of
complement activation remain confined to the initiating. Ag
without damaging other cells.

When considering the in vivo role of complement, two
important points should be borne in mind:
1.All complement component are acute phase proteins and
synthetic rates are increased within a few days of injury or
infection, most components are synthesized by the
macrophages in the liver.
2.There is considerable interaction between thecomplement
system and other pathways such as the clotting system,
fibrinolytic and kinin pathways.

-Chapter three-
Immunopathology
Body immune responses are normal defense mechanism designed to
protect the body from various environments factors, but the diseases
may result from :
1 In adequate immune response.(immunodeficiency).
2 In appropriate immune response.(autoimmune diseases ,Graft.
rejection).
3 Excessive immune response (hypersensitivity).
4 Amyloidosis.

1) In adequate immune response:
Result from immunodeficiency states there are 2 classes of
immunodeficiency syndrome:
1- Primary immunodeficiency at birth due to genetic disorders.
2- Secondary immunodeficiency during the life (acquired).

Primary immunodeficiency:
1 Transient hypogammaglobulinemia this occur in infants during 3-6 month
of birth, in which breakdown of maternal IgG it is considered physiological
hypogammaglobulinemia, and occur when infants unable to synthesize IgG
level so child become susceptible to recurrent pyogenic infection.
2 X-linked agammaglobulinemia (Bruton disease) it is a genetic disorder in
which failure of B cells maturation result in absence of antibodies, the
disease mostly occur in males so suffering from recurrent bacterial infection.
3 Isolated IgA deficiency:
There is reduction in IgA level but other antibodies are normal level.
4 Hyper IgM syndrome:
In normal condition IgM and IgD produced first against protein antigen
(Ag), followed by IgG,IgA and IgE antibodies (Ab). Patient with this
syndrome have normal level of IgM or abnormal level of IgM Abs but fail to
produce other Abs such as IgG, IgA, IgE, although IgM important for the
fixation of complement for activation and opsonization bacteria.

5 IgG subclasses deficiency :
Selective of IgG (IgG1 ,2, 3, 4) are easily missed because IgG1
contribute 70- of total IgG-IgG2 predispose the individuals to respiratory
infections and meningitis . IgG2 deficiency occur together with IgG4 and
IgA. Similarly IgG1 and IgG3 are commonly seen deficiency together.
6 Thymic hypoplasia (diGoeorge syndrome)
Affective T cells due to hypoplasia of thymus glands occur
together with hypoplasia of parathyroid gland so hypocalcemia, tetany,
cardiac malformation, facial abnormalities.
7 Severe combined immunodeficiency:
This inherited either autosomal or x-linked occur due to failure of
development of B and T cells, therefore thymus is small and body lymphoid
tissue are also small so children are susceptible to candida thrush,
pneumonia, diarrhea.
8 Defects in neutrophils and complement system.

Secondary immunodeficiency :
More common than primary, it occur during life, caused
by:
1 Protein loss (nephrotic syndrome ).
2 Impaired protein synthesis, malnutrition.
3 Lympho proliferative disease lymphoma, leukemia.
4 Multiple myeloma.
5 Immunosuppressive drugs.
6 Splenectomy, tonsillectomy.
7 Infections such as cytomegalo virus, Measles, rubella,
infectious mononucleosis, viral hepatitis.

Acquired immunodeficiency syndrome (AIDS)
It is retroviruse disease caused by human immunodeficiency virus
(HIV) characterized by:
1- Immunosuppression leading to opportunistic infections .
2- Secondary tumors.
Neurological manifestations:
The diseases is worldwide, about 20 years ago discovered
and more than 22 million people died.

Three major routes for the transmission of
virus:
1- Sexual contact.
2- Parenteral inoculation drugs.
3- hemophilia.
4- blood transfusion.
5- Infected mother to newborn.
Cause:
retrovirus belong to lenti virus family (HIV 2 types ) HIV1 in
USA, Europe, central Africa where HIV2 in west Africa.

Pathogenesis:
Two major targets for HIV immune system and central nervous system.
❖In immune system:
Aids lead to impair cell mediated immunity. It distruct CD4+ lymphocytes and
decrease helper suppressor T cells ratio.
Virus has selective tropism for CD4+ and macrophages and
dendritic cells. Where as viral envelope bind to other cells to enhance cell
entry. The virus core enter the cytoplasm have genes undergoes for reverse
transcriptase in which complementary DNA making and enter nucleus of cells
as a latent provirus DNA transcribed to from complete virus, bud from the cell
membrane and death of the cells.
HIV colonizes the spleen, lymph node, tonsils. The T cells, macrophages and
dendritic cells represent reservoir of infection.
❖In central nervous system:
Virus carried into brain by infected monocytes in brain microglia (equivalent
macrophages) is the target for HIV. In brain the
neurological deficit is caused by indirect viral products, cytokines
produced by macrophage/ microglia.

Clinical phases:
1 Primary infection:
At the beginning when viral replication in body organs, an
immune response developed with increase virus infected CD8+ to replace dying T cells,
followed by decrease CD4+ / CD8+ ratio, resulted in influenza, skin rash lymphadenopathy.
2 Asymptomatic phase (incubation period):
In this phase the immune system is intact but viral replication
continued, this stage may still for years, patients have AbS and transmit the disease.
3 Aids related complex:
In this CD4+ infected cells increased, their function impaired,
their number in blood fall to 400 cell/ UL
So malaise, fever, night sweating weight loss, diarrhea and lymphadenopathy . Impaired
CMI and CD4+ so fungal infection, salmonella and hemophilus are sever.
4 Aids (crisis phase):
In which fully developed immune deficiency so fatigue, fever,
weight loss, lymphadenopathy and diarrhea, CD4+ cells is bellow 400/UL. So most of
opportunistic infection, secondary tumors and neurological manifestations occurred and
death.

Opportunistic infections:
Responsible for 80% of aids patients death it include:
1 Pneumocystis carinii pneumonia.
2 Recurrent candidiasis.
3 Cytomegalo virus infection mainly retinitis, enteritis.
4 Herpes simplex infection in mouth, perianal infection.
5 Mycobacterium infection.
6 Toxoplasmosis.
7 Cryptococcal meningitis.
8 Cryptosporidium- enteritis.

Patients with aids have high incidence of Neoplasms (Tumors):
due to defects in T cells so;
1 Kaposi sarcoma occur in association with human herpes virus 8
(KS) infect skin, lung, lymph node, GIT.
2 Non Hodgkins lymphoma occur in association with (EBV)
Epstein bar virus. It affect brain, lymphoid tissue.
3 Cervix-uterus carcinoma tissue it occur with papilloma virus.

2) In appropriate immune response
Transplant rejection , organs transplantation used to
treat irreversible diseases of kidney, liver, heart, lung
and bone marrow. The action of immune system
destroy the transplanted tissue by HI and CMI
directed against the MHC Ag (HLA) of donor graft
endothelial cells are rich with MHC (HLA) Ag and
blood group Ag.

Types of transplant rejection:
1 Hyper acute rejection:
Occur within minutes to few hours. There is wide spread
thrombosis, focal necrosis, it formed due to reaction of preformed Abs
against graft Ags. These Abs developed either by :
1) Previous rejection of previous graft.
2) Women who develop anti HLA Abs against paterenal Ags.
3) Prior blood transfusion.
2 Acute rejection:
Occur within days or weeks, when stop immunosuppressive drugs
also occurred by HI and CMI against donor graft Ag. Particularity MHC class
II Ag. So renal failure with infiltration of CD4+,CD8+, vasculitis endothelial
necrosis, neutrophils infiltration, damage of B.V.
3 Chronic rejection:
Occur slowly during months and years of graft transplant. It is
slowly breakdown of self tolerance to graft due to inadequate immune
suppression. So increase creatinine level (renal dysfunction). Antimal fibrosis lead to
ischemic damage hyalinization, loss of glomeruli, tubular necrosis, atrophy and
interstitial fibrosis.

Transplantation of other organ liver, heart,
lungs, pancrease unlike of kidney it can
preformed with:
1- ABO blood grouping .
2- Absence of preformed Abs.
3- Body habitus example child not receive heart of adult.

2) Autoimmune diseases:
It resulted from reaction of immune system against self
antigen (Ag) i.e against body tissue or components. This
immune reaction either by autoantibody or cell mediated
immunity. In autoimmune diseases the normal mechanism of
tolerance for self (Ag) were break down. In self tolerance lack
of immune response to body own tissues. Some of
autoimmune diseases have genetic component i.e. some
diseases associated with particular HLA histocompatibility
type.
In other situation autoimmune diseased triggered by
infection such as rheumatic myocarditis cross Ag of
streptococcus with myocardial myosin.

Immunological tolerance:
both T.B cells bear self-reactive molecules (receptors )
recognize cell in tissue, cause damage resulted in
autoimmune disease. To avoid such as incidence both T.B
cells bearing such receptor must be either eliminated or
down regulated, so that the immune system become non-
reactive (i.e. tolerance to self Ag) this in normal individual.
The T cell tolerance is much more important than B cell
tolerance because both types of immunity depend on T
cell cooperation.

 Thymic tolerance: achieved through elimination all T cells capable for
recognize self Ag.
 Peripheral tolerance: involve several mechanism
1. Immunological ignorance:
Self Ag are invisible to immune system either sequestration of Ag in fluid such as
vitreous humour of eye or present in low level to CD4+ and Ag processing cells so
no immune activation, also slow gradual tissue break down during the apoptosis, so
No self Ag.
2. Anergy:
CD4 T cells require two signals for initiation immune response one signals from Ag
specific signals through T cell receptor, the other signals from Ag processing cell
such interaction occur in secondary lymphoid organs (L-node) if no 2nd signals
(from Ag- presenting cells) unavailable the only stimulation by T cell receptor alone
lead to apoptosis.
3. Suppression: self reactive T cell suppressed by suppressor T cells (CD8 +)
produced cytokines inhibited CD4+ helper activity.
4. B-cell tolerance: the production of self reactive Abs by these cells limited by
lack T cell help.

Break down of immunological tolerance( above)
lead to auto immune disease through the:
Overcoming peripheral tolerance when excess self Ag to
presenting cells or alteration of self Ag by viruses, radiation,
free radicals or during tissue damage(testis) due to trauma or
traumatic uveitis when these Ag kept sequestered in these two
organ against immune response.
Molecular mimcry:
Structured similarity between the self Ag and microbial Ags
(example) streptocouns- in systemic infection this cross
reactivity between self Ag and microbial Ag enhance T cell
immune response against body tissue such as
glomerulonephritis, rheumatic myocarditis .

Etiology of autoimmune diseases:
1- Genetic factors: through the :
a. Different autoimmune diseases are present in the same family like LE,
autoimmune hemolytic anemia and autoimmune thyroiditis.
b. Subclinical autoimmunity is common in family members. The association
between genetic factor and autoimmunity involve MHC (HLA) genes especially type
II Ag with autoimmunity.
2- Environmental factors: many factors trigger the autoimmunity:
1.Hormones so most of autoimmune diseases occur in female more than in male
and during reproductive years indicate estrogen had, role in autoimmunity, in
animal model remove ovary inhibit autoimmune disease, but giving estrogen
enhance onset of disease.
2. Infections: also associated with autoimmunity in some parts of world.
In animal model supported this association.
3. Drugs: also associated with autoimmune diseases such as in HLA-DR2 is
associated with penicillamine- induce myasthenia gravis where as an DR3
penicillamine induced nephritis so genetic variation is important similarly drug
induced SLE.
4. Ultraviolet- act either modify self Ag to become immunogenic or by enhancing
apoptosis with release of surface Ag (auto Ag) that hidden in the cell, such
exposure of these Ag on surface of cell lead to Ag- Ab reaction and tissue damage.

Classification of Autoimmune diseases:
1- Organ specific autoimmune diseases:
1. Vitiligo- skin- hypopigmentation .
2. Graves- disease- thyroid- hyperthyroidism.
3. Hashimotos disease- thyroid- hypothyroidism.
4. Addisons disease- adrenal- hypoadrenalocortism.
5. Autoimmune gastritis- stomach- pernicious anemia.
6. Type I diabetis militus- insulin producing cell (B. cells)- DM.
7. Myasthenia gravis- skeleted muscles- muscle fatigue.
2-multiorgan involvement of autoimmune diseases connective
tissue disease or collagen vascular diseases.
1. Systemic lupus erythematosis- skin, kidney, lung, joint, heart.
2. Progressive systemic sclerosis- skin, gut, lung.
3. Polymyositis dermatomyositis- skin, skeletal muscles.
4. Rheumatoid disease- joints, lungs systemic vessels.

Systemic lupus erythematosus:
One of connective tissue disease affecting female than male with young
ages, it involve multiple organs. It controlled by steroids or
immunosuppressive drugs, renal failure, current infections, CNS
involvement is the cause of death.
Etiology SLE:
a complex disease of multifactorial origin including genetic hormones
and environmental factors resulting T-B cells activation and produce
several autoantibodies due to main failure or less self tolerance.
Among the autoantibodies antinuclear Abs against nuclear Ag and auto
Abs against double stranded DNA both Ab are diagnostic. Auto Abs
against blood cells, platelets, lymphocytes, anti phospholipids Ab
(phospholipid important for blood clotting ) so Ab against phospholipid
are in patients with venous and arterial thrombosis.

Genetic predisposition for SLE.
1- High incidence in monozygotic twin than in dizygotic twin.
2- In the family members.
3- Positive association of SLE with HLA- II .
4- May accompanied with inherited complement deficiency.
Complement remove Ag-Ab complexes so lack of complement impair removal of
Ag-Ab complexes so tissue damage.
Non genetic causes:
1- Include environmental factors (drugs) most LE like syndrome in patients taking
drugs, procainamide, hydralazine.
2- Hormones sex hormones, female more than male affected with LE due to
estrogen effect.
3- Ultraviolet light- which induce damage DNA and promote cell injury with
release cell component augment the formation of DNA and anti DNA immune
complexes. and these immune complexes are detected in glomeruli ,also autoAb
against RBCS, platelets, WBCs .
the denatured nucleus of injured cell were ingulfed by neutrophils and
macrophage and detected easily (LE cells).

 Clinical manifestation of Lupus Erythematous :
1. Discoid skin rash.
2. Malar mash.
3. Photosensitivity.
4. Oral ulcer.
5. Arthritis.
6. Serositis.
7. Renal disorders.
8. Neurologic disorders .
9. Hematologic disorders .
10.Immunological disorders .
11.Presence of antinuclear Abs and anti DNA Abs.

Systemic sclerosis ( scleroderma):
It affect connective tissue of the different organs in many
system, more common in female than male in middle age.
The main abnormality excess fibrous tissue on the vessels
wall, perivascular fibrosis, lead to progressive ischemic
damage in many organs (skin was mostly affected
scleroderma), but GIT , lung , kidney heart. In the skin the
lesion in finger, upper extremities to upper arm, shoulder,
neck, face.

Rheumatoid arthritis (RA)
Multisystem connective tissue disease, the dominant effect are on the joints with
presence circulating Abs (rheumatoid factor ,RF), common in female than in
male, at 35-45 years, middle age) the disease no limited to joint but affect skin,
lungs, eye, blood vessels.
Pathological change:
Affect small and large joint of hands and feet.
rheumatoid synovitis swollen of synovium, mononuclear cells infiltration ( lymph,
macrophages and plasma cell) with lymphoid nodules (follicles ) formation
hypertrophy, hyperplasia of synovium, vascularity and fibrinous effusion in joint
space.
Articular cartilage destruction, replaced by granulation tissue (pannus) across the
surface of articular cartilage from edge of joint.
The inflammatory pannus cause destruction of adjacent bone together with
cartilage, the pannus fill joint space subsequent fibrosis, ankylosing of affected
joint, finally lead to secondary osteoarthritis especially in joint weight bearing
(knee joint). Destruction of tendon, joint capsule, ligament lead deformities of
joints.

Rheumatoid cutaneous nodules:
Firm , oval to rounded at the surface of farearm up to 2cm diameter
composed of fibrinoid necrosis.
Pulmonary involvement of RA lead to interstitial pneumonitis,
fibrosing alveolitis called honeycomb lung, also accompanied by anemia.
Pathogenesis of RA:
Genetic predisposition in first degree relative and in HLA-DR4 and or
HLA- DR1 . patients have rheumatoid factor (RF) is IgM directed against
fc region of IgG. RF (IgM) and IgG immune complex fix complement
attract neutrophils to area and type III hypersensitivity reaction. CD4 T
cells activated give cytokines;
1- Activate macrophages to produce proteolytic enzyme that cause
inflammation and tissue destruction.
2- Activate B cells produce (RF) autoantibody with IgG cause immune
complexes, subsequent joint injury.
3- Activated T cell induce osteoclast lead to bone resorption.

Juvenile rheumatic arthritis:
Occur in children like in adult cause destructive arthritis but
differ from destructive arthritis by:
Affect large joints.
Absence of RF.
No rheumatoid nodules.
Occur in association with HLA-B27.
Sjogren syndrome:
Characterized by dry eye and mouth
(keratoconjunctivitis sicca) and xerostomia) respectively
resulted from anti immune destruction of lacrimal (salivary
gland )it occur primary disorder or secondary with other
autoimmune diseases such as RA, SLE, polymyositis,
thyroiditis, multiple sclerosis and vasculitis.

Inflammatory myopathy
Characterized by immune mediated muscle injury and inflammation it
present;
1- Polymyositis.
2- Dermatomyositis.
3- Inclusion body myositis.
It occur alone or with other autoimmune diseases as systemic sclerosis it
affect the muscle of trunk, neck, limb and involve skin, eyelid in case of
dermatomyositis, so skin rash, periorbital edema histologically
lymphocytes infiltration with muscle degeneration.
Polyarteritis nodosa (PAN)
It is systemic disease characterized by inflammation and necrosis of wall of
arteries . The clinical effect from vessel occlusion lead to infarction. The
most organ affected kidney, GIT, liver, CNS, peripheral nerves, skin,
muscles. It is an immune complex mediated, there is association with
hepatitis B virus.

Autoimmune thyroiditis:
Hashimoto thyroiditis :
Is an autoimmune disease that result in destruction of thyroid gland and gradual
thyroid failure and painless thyroid enlargment . there is autoantibodies against
thyroglobulin and peroxidase. Hashimoto thyroiditis has a strong genetic
component . the autoimmunity effect of this disease:
1- Is depletion of thyroid epith by apoptosis .
2- Replace thyroid epith. By mononuclear cells infiltration with germina centers
and fibrosis.
3- CD8+ destroy the thyroid follicles.
4- CD4 T cells produce interferon gamma in thyroid tissue resulted in activation of
macrophages and damage follicles.
5- Binding of anti thyroid Ab (anti thyroglobulin and anti peroxidase) followed by
Ab dependent cellular cytoxicity. The disease associated with hypothyroidism in
middle age women, in area with normal iodine level diet patient with hashimoto's
are increase risk for developing other autoimmune disease risk (autoimmune
adrenalitis and type1 IDM), SlE…. Myasthenia gravis, Sjogren syndrome, also
thyroid carcinoma and B cell lymphoma in thyroid gland occur with hashimoto
disease. (in hashimoto's more T3, more T4, less TSH). Hashitoxicosis at
beginning later on less T3, less T4, and more TSH ) later on and Decrease
radioactive iodine uptake by radioiodine scan.

Subacute lymphocytic thyroiditis:
called painless thyroiditis post partum thyroiditis i.e after
pregnancy . Mild hyperthyroidism in middle age women. The
patient have circulating auto Ab against peroxidase some
cases can evolve into hypothyroidism and thyroid histology
similar to Hashimo thyroiditis with diffuse lymphocytic
infiltration replace thyroid tissue.

Granulomatous thyroiditis:
De Quervian thyroiditis ,also occur in middle age women , it believed to
be triggered by viral infection, it mostly occur in summer in association
with other viral infection measles, mumps, adenovirus, other viral infection
when exposure to viral Ag or thyroid Ag following virus induced tissue
damage , cytotoxic T cells cause damage to thyroid follicles in contrast to
autoimmune thryroid disease , it is immune mediated viral initiated
process associated with pain granuloma.
The thyroid gland enlarged due to early active inflammatory response ,
with lymphoid follicles replaced by lymphocytes and activated
macrophages with multigiant cells formation and plasma cell replace the
damaged follicles together with fibrosis. Similarly have more T4,more T3 ,
and low less TSH similar to Graves disease but radioactive iodine up take
decreased .

Riedel thyroiditis:
With fibrosis involving the thyroid gland the presence of
hard and fixed thyroid mass cause simulates thyroid
carcinoma. It may be associated with fibrosis in other sites
of body such as in retro peritoneum a manifestation of
systemic autoimmune IgG4 related disease .

Graves disease Hyperthyroidism:
Is most common cause of endogenous hyperthyroidism
characterized by;
1- Diffuse enlargement of thyroid gland ( thyrotoxicosis) opthalmopathy
and dermatopathy (pretibial myxedema).
2- It is an activation of thyroid epith. Cells by autoantibodies to TSH
receptor that mimic TSH action (thyroid stimulating immunoglobulin ) .
3- Diffuse hyperplasia and hypertrophy of follicles and lymphoid
infiltration , glycosaminoglycan deposition and lymphoid infiltration
responsible for opthalmopathy and dermatopathy .
4- Laboratory features less TSH more T3 , more T4.
5- In women more than male with age 20-40 years old.

6-Genetic factor important in graves disease in
monozygotic than dizygotic twins similar to Hashimoto
thyroiditis .
7- Hyperthyroidism occasionally resulted from increase T3(
T3 thyrotoxicosis) but T4 may be decreased in those
patients.
8- In pituitary associated (secondary) hyperthyroidism TSH
–normal or raised , during treatment with thyrotropin –
releasing hormone (TRH) lead to increase TSH level(normal
rise) and excludes secondary hyperthroidism.

9- Autoimmunity are important in exopthalmos protrusion of eye ball
(opthalmopathy ) due to :
1. Infiltration of retroorbital space by mononuclear cells.
2. Edema and inflammation swelling extraoricular muscles .
3. Accumulation of extra cellular matrix component such as hyaluronic acid
and chondroitin (glycosaminoglycans) under effect of CD4+.
4. Fatty cells infiltration these change displace eye ball forward, all these
changes interfere with extraoric ular muscle function.
Histologically :
thyroid acini epith showed hyperplasia epith tall and project in the lumen
with papillae, lymphoid (T,B cells) infiltrate the interstitial tissue with
germinal centers, administration of iodine cause involution of epith.
Treatment with propylthioracil stimulate TSH secretion and reduce
hyperplasia and hypertrophy of epith.

The dermotapathy and pretibial myxedema due to:
lymphocytes infiltration and glycosaminoglycans deposition smilar to
exopthalmia.
Graves patients are at risk for developing other autoimmune disease
such SLE, pernicions anemia, type 1 DM and Addison disease other
disease heart, hypertrophy and ischemic changes , thyroid myopathy ,
over activity of sympathetic nervous system.
 In grave disease more increase iodine uptake by radioiodine scan.
 Treatment by propylthiouracil, radioiodine and surgery.

Type 1DM: (diabctes mellitus):
Autoimmune disease, in which extensive distruction of Beta
cells in pancrease and insulin deficiency there is circulating
auto Abs against Beta cells Ags of panecrease and against
insulin detected in affected patiens.

Addison disease
1- primary chronic adrenocortical insufficiency
(autoimmune adrenalitis)
Resulted from destruction of :
Adrenal cortex, both sexes affected but much common in whites and women. In
which auto Abs against steroidogenic cells cause their destruction and
autoantibodies against steroidogenic enzyme (21 hydroxylase, 17 hydroxylase )
so histologically scattered residual cortical cells in C.T network and lymphocytes
infiltrate, it occur with either autoimmune;
1- Polyendocrine syndrome type1 autoimmune polyendocrinopathy , candidiasis
and ectodermal dystrophy) with mucocutaneous candidiasis, abnormalities of
skin, dental enamel and nails (ectodermal dystrophy) with organ specific
autoimmune disorders (autoimmune adrenalities , hypoparathyroidism,
hypogonadism, pernicious anemia) with destruction of target organs.
2- Autoimmune polyendocrine syndrome type II occur in association with
adrenal insufficiency, autoimmune thyroiditis or type 1DM but not candidiasis
and not ectodermal dystrophy and not autoimmune hypoparathyroidism
develop.

 In Addison disease Autoantibodies against IL17, IL22 which produced
by TH I7 these cytokines important for defense against fungal
infection so candidiasis develop in addison disease.
 Autoanti bodies against steroidogenic enzyme 21 hydroxylase and 17
hydroxylase. These autoantibodies are important in destruction of
these cells.
 In Addison disease the level of mineralocorticoid and glucocorticoid
are decreased, so weakness fatigue, GIT disturbances, K+ more
(retention)less Na+ (loss) and hypoglycemia due to decrease
glucocorticoids.
 Hyper pigmentation of skin, sun exposed area, neck. knee, elbow and
knuckles (at pressure point) is pathognomonic, caused by elevation of
proopimelanocortin (POMC) which derived from pituitary gland and
precursor for ACTH and melanocytes stimulating hormone ACTH high,
skin pigmentation.
 In contrast the hyperpigmentation not occur in person with
adrenocortical insufficiency caused by primary pituitary or
hypothalamus disease.

2- Secondary adrenocortical Insufficiency:
Any disorder in pituitary gland and hypothalamus reduce
ACTH lead to hypoadrenalism characterized by no
hyperpigmentation , low cortisol and androgen level but normal or
near normal aldosterone synthesis, normal Na and K.
Decrease ACTH level can occur alone by which differentiated between
Addison (normal level) and secondary adrenocortical insufficiency
(low level(.
In addison the destruction of adrenal cortex reduce response to
exogenous giving ATCH whereas in secondary hypofunction there is
prompt rise in plasma cortisol level.

Autoimmune gastritis:
1- Is characterized by antibodies to parietal cells and intrinsic factor
seen in serum and gastric mucosa.
2- Reduced pepsinogen concentrction.
3- Endocrine cell hyperplasia.
4- VIT B12 dediciency.
5- Defective gastric acid secretion (achlorhydria).
Loss of parietal cells , CD4 against parietal cell component cause injury
mucosal damage of body and fundus and mucosal atrophy,
lymphocytes and macrophage infiltration together with plasma cells in
association with lymphoid aggregation , also intestinal metaplasia with
goblets cells and columnar absorptive cells in mucosa.

3) Hypersensitivity or immunological injuries:
1- Type I hypersensitivity reaction or anaphylaxis:
Occur when exposure to an Ag result to formation IgE bind on mast cells when
subsequent exposure to same Ag degranulation of mast cells and release of
mediator increase vascular permeability so edema and smooth muscle contraction.
It occur in two phases;
1- Early within 5-30 minutes.
2- Late phase 2-24 hrs with mononuclear cells, aosinophilis and neutrophils
infiltration causing mucosal damage.
Among mediators:
1. Histamine.
2. Serotonine.
3. Lipase.
4. Proteinase.
5. Kinins.
6. Eosinophils chemotactic factor.
7. Neutruphils chemotactic factor.
8. Leukotrein and prostaglandine.
Clinical examples:
Reaction to penicillin , bee stings lead to skin rash, nausea, vomiting , facial
swelling , hypotension, tachycardia.

2-type II hypersensitivity , cellular cytotoxicity or cellular lysis:
Antibodies directed against Ag on cells or extra cellular matrix Ag either
endogenous or exogenous their mechanisms:
Complement dependent reaction in which Ab bound to Ag and fix
complement , cause cell lysis by promote phagocytosis.
Ab dependent cell- mediated cytotoxicity.
These include neutrophils, eosinophils, macrophages and natural killer cells
have receptors for IgG and mediate removal of Ag.
Clinical examples:
Blood transfusion reaction, autoimmune hemolytic anemia.
Ab mediated cellular dysfunction.
Abs them self affect function of Ag. Examples graves disease is due to Ab
activate thyroid stimulating hormone receptor, result in hyperthyroidisim
myasthenia a gravis due to Ab aginst acetylcholine receptor impair
neuromuscular transmission.

3- Type III hypersensitivity:
The Ab bind to Ag forming the immune complexes (Ag either
exogenous- viral protiens or endogenous DNA . the immune complexes
from in situ in tissue or circulate in blood and deposited and cause
tissue damage. The immune complex activate complement system and
enhance the immunological tissue damage examples:
glomerulonephritis.

4- Type IV hypersensitivity :
T cell mediated delay type hypersensitivity is caused by inflammation resulting
from CD4+ T cells and killing by CD8+, the inflammation is chronic and
destructive.
* APCs macrophages and dendritic cells cytokines activate CD4+ T cells to
secrete IL2 (act as autocrine growth factor ) for inducing Ag stimulated T cells.
* APCs activate and differentiated Ag stimulated T cell to TH1 , TH 17.
* APCs cytokines also induce IL12 which differentiated CD4+ to TH1 to secrete
IFN-𝜎 , it promote further TH1 and activate macrophages to induce tissue
damage, granuloma, fibrosis and give IL17 to recruit leukocytes to promote
inflammation .
• APCs cytokines ( IL1 , IL 6 and close relate to IL12 (1L23) stimulate T cell to
differentiated to TH17 ( has greater neutrophils component ) and memory T
cells.
Clinical examples:
T.B , leprosy, fungal and parasitic infection.

5- Cell mediated cytotoxicity :
The sensitized CD8 cell kill Ag bearing cells such as viral infected cells
or tumor cells the Ag represented by MHC I major histocompatibility
complex 1 Ag.CD8 kill Ag bearing cells by either perforin produce
holes in plasma membrane of cell bearing Ag or tumor cells or by
activation of complement system.

4- Amyloidosis :
Amyloid is a hyaline material deposited in intercellular spaces around cells
rather than in cells, special stain of amyloid is congo red.
Chemical nature of amyloid :
1- AL. amyloid light chain derived from plasma cells (Amyliod light
chain protein) in immunological disorder.
2- AA . amyloid associated protein amyloid A protein derived serum
protein precursor formed in liver in chronic infections .
3- AB in brain Alzheimer disease ( Amyloid B protein ) or (beta
amyloid protein) .
4- transthyretin ( TTR) serum protein bind to *thyroxin and retinol ,
trasport and deposited in heart (heredo familial amyloidosis ) .
5- B2 microglobulin is component of MHC class 1 molecules occur
with long term hemodialysis.
*Accumulated in : spleen, kidney and liver .
In H&E amyloid stain eosinophilic but in congo red pink colour under
light microscope but green birefringence under polarizing microscope .

Causes :
A. long continued infection such as T,B and leprosy .
B. prolonged immunological reaction in which hyperglobulinemia .
Organs involved are mostly :
A. Spleen either focal in white pulp termed sago spleen or diffuse involve all
splenic tissue i.e. red and white pulp termed bacon amyloid .
B. Liver occur in midzonal region of liver lobules in spaces between liver cells
and sinusoid endothelium .
C. In kidney amyliod deposited in glomeruli and in the wall of blood vessels .

Amyloid may be :
A. Primary → immunological associated with multiple myeloma
(malignant plasma cells ) associated with myeloma protein ( M protein )
and light chain amyloid known as bence jones protein .
B. Secondary amyloid occur with chronic infection .
C. Endocrine amyloid in case of thyroid carcinoma and pancreatic
carcinoma .
D. Familial or hereditary amyloid genetic disease .
E. Senile amyloid of aging amyloid .

Chapter Four
Infection and immunity
Factors influence the extent and severity of infection include:
1- factors related to the microorganisms:
a- dose degree of exposure.
b- virulence of organism.
c- Route of entry,
2- factors related to host:
a- integrity of non- specific defenses.
b- competence of the immune system.
c- genetic capacity to respond normally to a specific organisms.
d- evidence of previous exposure (natural or acquired).
e- existence of co- infection.

Normal resistance to infection:
1- Non- specific resistance (natural resistance) refers to:
a- barriers.
b- secretions.
c- normal flora.
d- phagocytes and complement.
* mechanical barriers – are highly effective and their failure often result in
infection e.g: defect in mucocilliary lining of respiratory tract (as in cystic
fibrosis) are associated with an increased susceptibility to lung infection
However many common respiratory pathogens have specific substanees
e.g: the haemagglutinin of influenza virus which help the attach of virus to
epithelial cells, and so breach physical barriers.
* Secretions including tears , mucus, gastric acid , bile , enzyme , acidity of
urine .
* Flushing of urine, cilia , alveolar mearophages, skin barriers, all these are
non specific defense mechanisms

Phagocytic cells:
Are to infest invading microorganism, kill and digest
them, A prompt response to infection is achieved by:
1- concentration of phagocytes at site of infection.
2- having population of cells rapidly mobilize during
inflammatory response.

Polymorphonuclear cells:
Invading microorganisms trigger an inflammatory response with a release of
chemotactic and other factors attract neutrophils during adherence to
andothelial cells. Squeeze out of blood vessels and migrate towards the
inflammatory site, several neutropenia or neutrophils dysfunction is associated
with life – threatening infection caused by staph, gram negative bacteria or fungi
phagocytosis is promoted by opsonins (Ab, IgG or complement), non opsonized
bacteria still be recognized by phagocytes receptor for sugar present in bacterial
cell wall. The phagocytic receptors with complement are important in
phagocytosis of bacteria before specific immune response begin and before
opsonizing Ab has been made, polymorphonuclear cells are short live in infection
result in increase out put of bone marrow So polymorphonuclear leukocytosis in
blood, the immature cell are also released in blood described as a shift to the left
on blood film.

Macrophages:
Accur in the subepithelial tissue of skin and intestine and lining alveoli in
the lung when ,microbial agent invaded blood or lymph the fixed
macrophages lining the sinusoids (kupffer cells) in liver, in the sinus of
lymph node and in spleen (RE cells lining red pulp), these macrophages
induce cytokines against bacterial agents among these cytokines
(interleukin , tumor necrosis factor) is implify in immunity and infection
process, most pathogenic microorgamsm have evolved methods of
resisting phagocytic cells e.g staph. aureus give exotoxin kill phagocytic
cells and lead to pus.
Some microorganisms have polysaccharides capsule inhibit phagocytosis
e,g in streptococcus pneumoniae , other organism like T.B even ingested
by phagocytic cells but resist intracellular killing, phagocytosis can
proceed effectively when bacteria opsonized by IgG, IgM or complement.

Heat shock proteins (HSP):
Family of proteins has been described which ebable cells to resits a
variety of insults, Both pathogens and host cells use similar HSP to
protect themselves from each other. HSP are produced when a cell is
exposed to a sudden increase in temperature, to anoxia, or to the
reactive oxygen radicals produced by phagocytic cells during attempted
intracellular killing of microorganisms, many pathogens including
protozoa, helminthes and fungi have to face sudden major temperature
shifts as they move from one environment into human body- e.g:
leishmania must survive a temperature rise from 25C̊ to 37C̊ when it
transmitted from the sandfly into human body this heat shock may cause
unfolding of vital protein within the cell and one major task of HSP is to
prevent or reverse these events a role termed housekeeping, mutants
that readily express HSP are highly resistant to oxidizing agents and to
heat.

2- specific resistance :
a- Hurmoral immunity:
individuals with antibody deficiency are prone to repeated infection
with pyogenic bacteria, but replacement therapy with immunoglobulins
markedly reduee the frequency of these diseases, the course of
infections with many viruses (varicella or measles) is normal in these
patients, however in the absence of mucosal antibody (IgA) there is
susceptibility to some enteroviruses.
b- Cell mediated immunity (CMI):
it is important in viral and in intracellular bacterial infection more then
humoral immunity.
Patient with impaired cell mediated immunity recover from most
bacterial infections but have difficulty in controlling and eradicating
infections with viruses such as measles , varicella and herpes, they also
show increased susceptibility to mycobacteria , listeria and some fungi.
Recurrent infections or infection by unusual organisms suggest the
possibility of an immunodeficiency.

Viral infections:
Viruses have unique properties:
1- They can infect tissues without inducing inflammatory
response.
2- They can replicate in cells, throughout the life without
causing cell damage.
3- Some time they interfere with specialized cell function
without causing detectable damage e .g: Polioviruse)
4- Occasionally the virus causes tissue damage or interfere
with cell development and virus disappears from body.

Immunological reactions:
Thus of 2 kinds, those directly against virion, humoral immunity (viral
neutralization) to prevent viral attachment to target cell, this is a function
of IgG in the extracellular fluid IgM in blood and IgA on mucosal
surfaces.(secretory IgA) also complement mediated phagocytosis and lysis
of viruse ,some viruses e.g: EBV bind to C1 with activation of classical
pathway and subsequent virion lysis with absense of Ab. Cell mediated
immunity (CMI) are important for cell infected with virus rather than free
viruses, so viral sensitized lymphocytes recoginize the viral Ag in
association with MHC – Class1 glycoprotein's and the cytotoxic T cell lyse
the virally modified cell and limit the disease by eliminate production of
infectious progeny.

T cells are therefore concerned with recovery from virus infections. Most
viral infections are self – limiting Recovery from acute viral infection
usually produce long – term immunity and secondary attacks by same
virus are uncommon.
Resently attention has focused on the possibility that persistent virus
infection cause persistent generalized symptoms e.g. EBV infection may
last some years but recovery is invariable, However the post vival fatigue
syndrome , also called the chronic fatigue syndrome or myalgic
encephalomyelitis (ME) is controversial subject. ME describes sever
prolonged , diabling fatigue often associated with myalgia and mood
and sleep disturbances.

Direct effects of viruses:
1. Clinical important of viral Infections depend on not only the number of cells
destroyed but also on the function of those cells for e.g: destruction of few
number of highly specialized cell function such neurotransmission and
immunoregulation can be diabling or life threating , whereas, destruction of
large number of less specialized cells such as epithelial cells has less drastic
results.
2. Viral receptors and virus receptor interaction, viral tropism is increasing for e.g:
EBV use C3d receptor (CR2) and HIV use CD4 receptor in order to gain entry
into target cells.
3. viruses are side cells e.g: Poliovirus, adenovirus or their products can killed the
cells by either block enzymes needed for cell replication or metabolism, some
viruses disturpt intracellular structures such as lysosmes releasing lethal
anzymes, some viral protens insert into cell membrane can alter its integrity or
posses fusion activity and cause cell to from syncytia e.g: measles virus.
* Some viruses, alter he specialized function of the cells without killing it such as
belong to CNS or endocrine system for e.g: dementia caused by HIV.

Viral strategies to evade with immune response:
1- Ag variation: by which the virus can evade the Ab response by
modifying the structure of the haemagglutinin and neuraminidase in
two ways:
Agic drift and agic shift, this accurse for e.g: in influenza A viruse (RNA) contain
these coded proteins (heamagglutinin and meurominidase) inserted in lipid
envelope of the virus.
A- Agic shift: major structure change of the heamagglutinin and neuraminidase,
four such alteration occurred in Spanish influenza epidemic 1918 Asian Influenza,
1957, Hong Kong Influenza 1968 and Russian influenza 1977.
B- Agic drift: minor structure change caused by point mutation altering an Agic
site on haemagglutinin, such mutations probably account for minor epidemic of
influenza, occurring most winter.

2- virus persistence and latency:
this occur when the provoked IR does not clear the virus, a low grade infection
with persistence shedding of infectious virus may result for e.g hepatits B virus
can persist for months and years with continuous carriage by the liver.
Alternatively the virus may inter a latent phase when viral genome remain within
host cell but no expression of viral Ag occurs. for e,g herpes viruses remain latent
under going periodic cycle of activation and replication, when the equilibrium
between the virus and host defenses is upset by other infections, metabolic
disturbances, Aging and immunosuppession. The virus may be activated then
express the disease.
Frequently the viruses remain latent in anatomically defined sites for e.g: Herpes
simplex virus in trigeminal ganglion (producing cold sore), varicella zoster in
dorsal root ganglion (cause shingles).

3- transformation of host cells, this occurs in oncogenic viruses,
some of these viruses establish latency among these viruses are:
a- Burkitt's lymphoma cells in which translocation between long arms of
chromosome 8 and 14 (e,g EBV).
b- Nasopharyngeal carcinoma similar to Burkitt's lymphoma caused by
also EBV.
c- T cell leukemia viruse = human T Cell leukemia viruses.
d- Carcinoma of servix – Herpes simplex type 2 and papilloma virus of
human.
e- skin cancer papilloma virus.
f- Hepatocellular carcinoma e.g HBV and HCV.

4- some viruses interfere with IR by suppression it or infect the cell
of IR such as:
a- CMV infection which cause reasonably brisk and predictable Ab
response but CMI is depressed, So decrease interferon gamma and
lymphocytes transformation decrease.
b- measles virus replicate in activated T Cell with reduction of CMI, so
when accompanied with T.B lead to miliary T.B if no treatment.
C- Aids (HIV1 , HIV2) infect and deplete CD4+ lymphocytes macrophages
so immunosuppression and sever opportunistic infection is occurred.

Damaged caused by IR to viral infections:
There are several diseases caused by obnormal IR to viral infection such as:
1- Production of autoimmune phenomena:
Lead to auto immunohemolytic anemia (auto Ab) e.g infections monoculeosis
(EBV) which upset the self tolerance of the body by 2 ways.
a- polyclonal B cell activation
b- combination with host Ag to form new Ag and Ab recognize these
new host Ag as well as virally infected cell, persistence the viral infection
may cause autoimmune disease e,g: autoimmune liver disease following
HBV infection.
2- Production of inappropriate Ab e.g.:
Dengue hemorrhagic fever virus infect macrophages through their FC receptor
when bound with IgG enhance its entrance in these cells and cause damage, so
other viral infection easily occurred by these preexisting Abs.

3- Blocking Abs/ blocking complexes:
lead to subacute sclerosis pan encephalitis so Ab against viral infected cells cause
adverse reaction, antiviral Ab or immune complexes of virus Abs cause
prevention of sensitization of the lymphocytes to recognice viral Ags. so inhibit
CMI eg: Measles virus lead to Ab blocks the action of TC and TH and so no CMI
lead to e.g: sub acute sclerosing panencephalitis.
4- Immune complex deposition:
Occur when Ag- Ab and complement when present in intima of blood vessels
causing vasculites e,g with HBV infection, polyarteris nodosa and
glomerulonephritis. Similarly occurred with other unknown Viruses Also when
Ag- Ab- complement located in glomeruli or in joint causing arthritis.

5- Cell mediated damage
occur for e.g. : in some diseases such as measles, herpes, simplex and
varicella zoster in which small foci of these viruses elicit Rash (CMI or DTH)
which limit viral spread and replication of viral infection but not show the
typical Rash, e.g. Measles virus, herpes simplex and Varicella zoster both
cause rash coxsackie virus cause myocarditis, mumps cause possible
menigo encephalitis, some uknown viruses cause some encephalitides.
A classical example of damage mediated by CMI is the lymphocytic
choriomeningitis virus proliferate in many tissue of mice including CNS
with few ill effect (in neonatal life) , but virus inoculation in brain of adult
mice lead to meningoencephalitis with cerebral damage limited by
measures which impair CMI, if the animal reconstituted with T cell from
immune donor restore the infection. the cytotoxic T cell from donor
(immunized) lyse the infected brain cells which express virus coded Ag –
this indicate that CMI contribute encephalitis in adult mice similarly seen
in human virus infection.

Bacterial infection:
Normal IR to bacterial infection occur due to two major groups if bacterial
Ags:
1- soluble products (diffusible) of the cell e.g: (toxins).
2- Structural Ags that are part of the bacterial cell wall such as
(lipopolysaccharides):
many bacterial Age which contain lipid associated with cell wall. Presence of lipid
potentiate the immunogenicity of the associated Ag most of bacterial Ags are T –
Cell dependent e.g.: required helper T-cells for Hi and CMI.
Other bacterial Ags are T- cell independent such as pneumococcal polysaccharides
because high M.Wt and have multiple repeated Ag. Determinants in children
adequate IR to these Ag can take 4-6 years to develop. So children are susceptible
to disease by these capsulated bacteria.
The interaction of bacteria with IR (Bacteria and immune Response):
1- stimulation of protective immunity.
2- Immune suppression.
3- disadvantage of IR cause tissue damage.

Protective immunity:
The difference in clinical picture of the any disease related to immune
status and Age of patient e,g: streptococcus in young children cause fever
nasal discharge , but in adult children and adults cause more acute
tonsillitis, this belong to previons exposure to streptococcus and
modified response due to preformed Ab. to streptococcus toxins and
enzymes.
The protective immune response that resulted from production of
specific Abs against bacterial Ag within 4 day of infection for e.g:
Antistreptolysin (O,S Ag) and antistreptococcus DNAse B are two valuable
streptococcal Abs test for clinical use e.g: ASOT is generally raised after
throat infection but not after skin infection, but anti DNase B is Important
reliable test for both skin and throat infection and useful for diagnosis of
post streptococcal glomerulonephritis, some bacterial products
(endotoxins) stimulate polyclonal activation of B cells (powerful
stimulators) this rise the immunoglobulin in prolonged infection such as
in TB is due to this type of stimulation of polyclonal B cells since increase
in specific Ab from small proportion of total immunoglobulins.

* Immune suppression:
This occurred due to some bacterial Ags which directly influence the outcome of
IR to infection during which the host become susceptible to a secondary
pathogens such as TB, pulmonary aspergillosis.
* Immune damage:
Also caused by various streptococcal products such as:
1- specific toxins (O,S, pyrogenic exotoxin) which lyse tissue and circulating
leukocytes.
2- specific enzymes: such as streptokinase and hyaluronidase, these promote
the spread of infection.
3- Surface components of streptococcal cell wall (M. proteins) and
hyaluronic acid all these are immunogenic, but M proteins are virulent factor
in addition to it is immunogenic.
4- Local inflammation lead to circulating neutrophils and their infllteration
cause tissue damage and pus fornation.
5- streptococcal infection: can produce toxic shock syndrome of hypotention
and multiorgan failure with fatality rate of 20% many of there strains that cause
toxic strept syndrome produce streptococcal pyrogenic exotoxins A which
responsible for fever, organ damage and also for rash of scarlet fever.

Bacterial Evasion of immune Response:
Bacteria survive in the host, if IR kill them at slow rate than rate at which they
multiply so bacteria have evolved many mechanisms for achieving this evasion.
1- Virulence determinants:
Are the structures that enable successful adherence at mucous surfaces,
penetration, tissue growth, inhibition of host defenses and tissue damage,
Determinants inhibiting host defenses called aggressins are important for long
term survival for e.g.: pneumococcal and meningococcal polysaccharides Ag can
inhibit the ingestion of bacteria by phagocytic, cells , many aggressins are Agic
and appropriate IR abolishes their effect on host defenses.
2- Agic Variation:
This more recognized in Trypanosoma brucei and influenza but also occur in
some bacterial infections e.g: tick bite relapsing fever due to multiplication of
Borrelia recurrentis . after a week Ab destroy the bacteria and fever subsides,
however Agic variants are formed after 5-7days (through bacteremic proportion
with consequent relapse of patients. Abs to these Ag variants eliminate the
bacteria and fever but further Ag variants are made again, the cycles recurs 5 to
10 times before disease subsides.

3- Some bacteria infecting MM surfaces posses protease
that hydrolyse IgA Abs e.g Neisseria gonorrhea Neisseria
meningitidis, Haemophilus influenza and strept. Pneumoniae
some times Staph. aureus produce enzymes (catalase) that
prevent them being killed inside phagocytic cells.
4- Bacteria may survive by sequestration in some phagocytic
cells where there not exposed to IR or antibiotic for e.g. :
salmonella typhi scarred tissue and avascular area of gall
bladder and urinary tract (chronic carriage).

5- Intracellular survival in macrophages occurs in some
chronic cases of IR, leprosy, Brucella, Nocardia. In
macrophages when killed mechanism is impaired the
ingulfed bacteria can survive.
6- cell wall- deficient (L) variants occur during chronic
and carrier states of some bacteria such as Streptococcus,
Brucella, Gonococcus, T.B L- form survive treatment with
antibiotics which interfere with cell wall synthesis and
provide a source of virulent normal forms of bacteria
when drug treatment stops.

Damage caused by IR to bacterial infection:
It is difficult to distinguish between the toxic effect of bacterial toxins
and damage caused by IR. The main bacterial agents associated with
rmmune damage to body tissue is e.g: Rheumatic fever after
streptococcal infection of upper respiratory traet in non treat patient
with genetic predisposition host most common in monozygotic than in
dizygotic twins and in whites with HLA- DR4 and in blacks with HLA=
DR2.
Rheumatogenic strain of streptococcus show certain characteristic
features:
1-they belong to M serotypes.
2- their M proteins contain epitopes share with human heart tissues.
3- epidemic rheumatogenic strains are encapsulated and form
mucoid colonies on culture.
4-these M- rich strains resist the phagocytosis by inhibiting
alternate complement pathway.

Children with rheumatic fever have high incidence of Abs against heart extracts,
so rheumatic carditis may caused by antistreptococcal Abs which cross react
with heart Ags.
Rheumatic fever not confined to the myocardium and lesions are found in heart
valves, jionts, B.V. skin CNS (chorea) ,
this found there is Ab moderate damage since cross reaction has been
demonstrated between:
1- streptococcal group A carbohydrate and glycoprotein of heart valves.
2- Other components of cell wall and human brain.
3- Glycoprotein of cell wall and glomerular basement membrane.
4- Streptococcal hyaluronidase and human synovial membrane.
5- M protein and cardiac sacrolemma and cardiac myosin.
6- Some sore throat patients develop . these cross reacting Abs without cardiac
disease while in animals passive transfer of Abs alone has not effect on organs
suggesting that the damage by streptococcus products is required for Abs to be
damging .i.e damage by Abs mediated and required streptococcal products Ag
or their cross reactive similarities.

CMI to cross reacting Ags:
May partly responsible for the complications since patient with rheumatic
fever show exaggerated CMI to strept Ag and non specific changes of
circulating CD4+ and CD8+.
The relationship of streptococcal infection to acute post streptococcal
glomerulonephritis differs from that in two important respects:
1. Glomerulonephritis seems to occur only after infection with one of the
few nephritogenic strains whereas, several but not all serotypes of
group A strept. Are associated with rheumatic fever.
2. Available evidence suggests that post streptococcal glomerulonephritis
is caused by deposition of circulating immune complexes and not by
cross reacting Abs. The two conditions are rarely associated with each
other in epidemics that are caused by a single strain of known M.
serotype.

Many other bacteria and mycoplasma infections can also
trigger a self- damaging immune response.
Recently the role of heat – shock proteins (HSPs) in these sequences has received
considerable attention these are abundant and extraordinarily highly conserved
proteins that have an assential role in normal cells function. They are also the
major Ag of many pathogens and so play a role in the immune response to
infection. The stress placed by the host on invading organisms lead to increased
HSP synthesis which generates Ag capable for triggering the IR .HSP 65 for e.g: is
a , major Ag of various bacterial pathogens causing human diseases including
leprosy: T.B,Q fever , Lyme disease and legionnaires disease. A cross reactive IR to
HSP 65 has been implicated in the pathogesis of autoimmune diseases T. cells
and antibodies reactive against epitopes shared by bacterial and human HSP are
undoubtedly present in normal individuals.
During microbial infections these T cells may be activated by exposure to
microbial HSP while human HSP are expressed on host cells stressed by the
infection. Recognition of these cells by T cells and Abs with specificity for shared
epitopes could trigger an autoimmune response.

In rats active immunization with HSP 65 fails to induce arthritis but
protect against subsequent attempt to induce arthritis by compete
freund's adjuvant (which contain killed mycobacterium tuberculosis ) here
T cells clones recognize an epitope of mycobacterium HSP 65 , One such
clones is arthritogenic l.e induce arthritis in irradiated rat where as
another is protective i.e induce resistance to arthritis in recipients this
model may be relevant to rheumatiod arthritis since HSP 65 is abundant
in human rheumatoid toints. High titers of Ab and T cell recposive to
mycobacterial HSP 65 are found in these patients. Particularly in younger
patients with juvenile chronic arthritis, the role of HSP in pathogenesis of
human autoimmune diseases remains unclear but encourages
speculation that immunization with purified HSP may able to alter the
course of certain autoimmune diseases;

Examples of disease caused by immune reaction to bacterial Ags:
Immune reaction Diseases
1- cross – reacting Ag (type II hypersensitivity )
a-human heart and group A
Streptococcus
Rheumatic carditis
b- human brain and group A
streptococcus
Sydenham's chorea
2- association of infective Ag with auto Ag (type II
hypersensituvity)
Mycoplasma Ag and erythrocytes Autoimmune hemolytic anemia
3-Immune complex formation (type III
hypersensitivity)
a-Subacute bactetrial endocarditis.
b- infected ventriculoatrial shunt
c- secondary syphilis
Vasculitis, arthritis, glomerulonephritis
d- gonococcal septicemia
e- meningococcal septicemia
Vasculitis ,arthritis
4- dedlayed type hypersensiticity rcactions (type
IV hypersensitivity)
T.B Pulmonary cavitations and fibrosis
Leprosy Peripheral neuropathy

Fungal infections:
Fugal infections classified in to three classes:
1- Superficial mycosis: infect the skin and M.M which caused by :
2- subcutaneous mycosis involve mycosis the adjacent tissue
such as skin and bone Causative agent Caused by sporotrichium
schenkii (sportrichosis) , Clinical Features ulceration and abscess
formation.
Causative agent Disease Clinical feature
Trichophyton Tinea corporis
Tinea pedis
Ring worm
Athletes foot
Candida albicans Candidiasis Valvovaginints and thrush

3- systemic mycosis pathogenic, Opportunistic.
Causative agent Diseases Clinical finding
1-Histoplasma
capsulatum
Histoplasmosis Pulmonary infection
2-Coccidioides immitis Coccidioidomyco
sis
Acute pneumonitis
3- Candida albicans Systemic
candidiasis
Bronchopulmonary disease ,
oesophagitis
4-Cryptococcus
neoformans
Cryptococcosis Meningitis , solid lung lesion
5- Aspergillus
fumigates
Aspergillosis Aspergilloma, cerebral abscess,
eye infection

Pathogenic fungi:
Mean that infection may result from contact with the
organism in any individual.
Opportunistic fungi: occur only in immunosuppressed host
e.g candida albicans are commonly found in the GIT from
mouth to the anus,infect skin M.M act as barrier to this
fungus, although PH, temp. of skin shedding rate of
normal flora important for prevent fungal colonization and
subsequent invasion.

Causes of candida infection:
1. Disturbances of GIT ecology due to antibiotic, traumatic or
hormonal change are important predisposing factor in
chronic superficial Candida infection.
2. Change in the host immune response is important factor
governing susceptible to systemic fungal infection,
Colonization of the susceptible host occurred when breaks
in skin and mucous membrane and fugal get access in these
sites or contaminated urinary catheters.

Immunity to Candida infection:
include precipitating Abs and CMI,
CMI are very important for controlling mechanism against
Candida infection (especially systemic candidiasis) since
the disseminated fungal infection occur in individuals with
impaired T cell function (decreased CMI) or neutrophils
dysfunction although rare in Ab deficiency.

Immune damage caused by immune reaction to fungi:
1- IgE mediated hypersensitivity reaction:
For e.g: Aspergillus when present in a persistent aspergilloma in which
fungus grow in lungs cavities after treatment of T.B the allergic
pulmonary aspergillosis develop IgE mediated hypersensitivity against
Aspergillus Ag. So bronchi are obstructed by fragmented mycelia and
eosinophils infiltration in bronchial walls.
2- Ag – Ab complexes:
Wher inhaled fungal Ag and preformed precipitating Abs present the
Ag- Ab complexes occur in lungs e.g: farmers lungs: this conditions
resulting from immune complex mediated to a fungus
(Micropolyspora faeni) present in mouldy hay.

Parasitic infection:
Immunity to protozoal infection:
If parasite elude the host IR and sufficiently virulent they kill the host
upon their own survival depend if they are too easily destroyed by IR,
their own survival is geopardized, the survival of any parasite depend
on balance between induction of immunity in the host and escape from
surveillance, parasite may have mutation in human which enable them
to resist the parasite e.g" Plasmodium falciparum cause malaria but in
sickle cell hemoglobin gene confers partial resistance to this parasites
and limit its multiplication within RBCs , whereas, in people with normal
Hb genotype (HbAA) are highly susceptible to this parasites.
Those with homozygous sickle cell genotype (Hbss) suffer from serious
and lethal sickle cell anemia, but those with hererozygous sickle cell
trait (Hb Sd) have a survival advantage in endemic malarial areas.

Patients react to protozoal infection by:
1. Early activation of macrophages monocytes: and release of the
eytokines such as TNF, IL6 , IL1. their combined actions cause fever,
leukocytosis, production of acute phase proteins such as C- Reactive
proteins (CRP). The fever itself host defense mechanism against parasites,
since in stages of malarial development is sensitive to elevated
temperature.
2. IgM. IgG abs are respond to protozoal parasites, it is not protective so
difficult in production of vaccine against protozoa and some protozoa can
survive in host cells such as malaria in RBCs. And hepatocytes and
leishmania survive in macrophages, these survival methods are not
accessible to Abs unless protozoal Ag secreted on host cell surface.
3. CMI: has proved difficult to evaluate in these diseases. Local DTH
account for localized disease in cutaneous leishmaniasis, but in visceral
leishmaniasis not prominent CMI reacting although sensitized T cells and
interferon- gamma are important in leishmaniasis but it is difficult to
evaluate in these diseases.

Mechanism of protozoal survival:
There are 4 ways in which protozoa can evade or modified IR:
1-Agic variation for e.g: Trypanosome brucei (sleeping sickness) transmitted by
tsetse fly, after infection the number of parasite in blood fluctuated periodically, this
cycle of parasitemia remission and recrudescence due to destruction by host Abs
followed by emergence of parasite and express different surface Ag or virulent surface
Ag or variant surface glycoprotein's (VSG) 10×106 molecules of VSG, are same on
single parasite not other, Ab production after each parasitemia are specific one for VSG
only. Because the parasite posses number of genes that code for it's variant surface
glycoprotein and can shed the old coat of VSG and put a new one not recognized by.
Abs. this type of Agic varlation is known as phenotypic variation and is in contrast to
genotypic variation in which new strain periodically results in an epidemic as in case of
influenza.
2- Agic modulation: by protozoa change their surface coat (Cap off) to elude the IR
within minutes to exposure to Abs and complements for e.g: leishmania parasites.

3- Suppression of IR: e.g: in malaria and visceral leishmaniasis produce soluble
Ag released by these parasites may inhibit non- specifically the host IR by directly
acting on lymphocytes or saturating the RE cells. Such Ag may effectively remove
the specific Ab, so preventing Ab to eradicate the parasites. Leishmania and
Trypanosoma have stages that refractory to complement mediated lysis e.g.
Typanosoma cruzi produce molecules that either inhibit the formation or
accelerate the decay of C3 convertases, so blocking complement activation on
parasite surface. Leishmania can resists lysis by serum (fresh serum) and can
down regulate the MHC- Class II on parasitized macrophages although CD8+
able to kill parasitized macrophages but spread of parasite (unkilled parasites)
from macrophages and infection continue.
4- Survival in macrophages: for e.g : Trypanosome cruzi, toxoplasma,
leishmania can survive in macrophages and grow inside it in which there is to
prevent fusion of phagocytic vacuoles (containing the parasites and lysosomes)
i.e inhibit phagosome lysosome combination e,g Toxoplasma whereas
Trypanosome inhibit or resist intracellular killing in macrophages. Leishmania
bind C3 activity and these molecules enhance binding this parasites to CR3
receptors on macrophages, the complement coat seems to reduce respiratory
burst on entry into macrophage and increase parasite survival, Also monoclonal
abs to CR3 receptor inhibit up take of parasite into safe haven.

Immunity to helminthes infection:
The immunological characters of helminthes
infection are:
1- Increased IgE.
2- Eosinophilia.
3- Mastocytosis.

There responses are regulated by CD4+(TH2).
1- Increased IgE production:
These occur in people live in tropical and subtropical countries where
helminth infestation is endemic those people show rise in IgE and
parasitic specific IgE are important in protecting the infected host. e.g:
Schistosoma mansoni IgE Ab react with helminth Ags and lead to
release pharmacologically active mediators from mast cells,
eosinophils and basophils these mediators cause loclal accumulation
of the leukolytes and augment their ability to damage the helminth
they induce local inflammation and induce contraction of smooth Ms
to aid expulsion of the parasites, However the parasitic specific IgE
induced by IL4 produced by CD4+ (TH2).

2- Eosinophilia:
This like IgE response, also regulated by (CD4+ T cells) but is driven by
IL5. Some parasitic materials is even directly attractant to the
eosinophiles these cells have effector role in helminth infection, they
attach to parasitic surface via IgG Abs or C3 and degranulate,
releasing major basic protein and eosinophilic cationic proteins which
cause holes in the integument of the helminth.
3- mast cells and mastocytosis:
These cells degranulated by bound IgE reacting with parasite Ag. And
release eosinophils chemotactic, factor of anaphylaxis inaddition to the
pharmacologically reactive materials released from eosinophils.
Basophils, and mast cells which are IgE mediated releasing.

Mechanism of helminth survival: or (helminth evade IR):
1. Agicdisguise:
This is important in helminth survival. For e,g: adult
Schistosoma disguise their surface Ag by synthesize host like
Ag such as α2 (aipha-2) macroglobulin to mask their own
foreigness, alternatively they may adsorb host molecules on
their surface, RBCs Ag, Immunoglobulin, MHC-Ag and
complement have all been demonstrated on outer layer of
Schistosoma.

2. Immunosuppression of T and B response:
Numerous immune mechanisms are directed against e.g:
young Schistosoma as it migrate from skin to B.V. in which
become mature, Schistosoma evade such attack by
releasing peptidase that cleave bound immunoglobin and
other factors that inhibit either T cell proliferatlon and
releasing interferon –gamma or mast cell signals required for
eosinophils activation.

3. Concomitant immunity or premunition:
Describe a form of acquired immunity in which the
established in fection persists but new infection is prevented
by immune mechanism, Schistosoma is again best e.g: adult
worm can live in the host for many years with evidence of
little or no immune response however the adult Schistosoma
do stimulate a response that prevent reinfection of the same
animal with immature from of parasites called cercaria the
disguise adopted by adult worm play an important role.

Damage caused by immune reaction to parasite:
1- immediate (type I hypersensitivity):
such as urticaria , angioedema found at the acute stage of Ascariasis
and in many other helminth infection, rupture of hydatid cyst during
surgery may release vast amount of Ag and trigger the anaphylactic
shock.
2- Type II hypersensitivity reaction:
caused by Ab to cell surface Ag, parasitic Ag which cross- react with
host Ag (host tissue) adsorbed on the parasitic surface may lead to
development of Abs which recognize self Ag such autoimmunization is
an important factor in the immunopathology of chaga's disease where
the cardiac lesions are thought to be due to in part at least to
circulating autoantibodies.

Damage caused by immune reaction to parasite:
3-Circulating Immune complexes:
The Immune complexes of parasitic Ag and host Abs cause tissue
damage seen in Malaria, Trypanosoma and Schistosomiasis. In some
cases chronic deposition of immune complexes lead to
glomerulonephritis.
4- Cell mediated immunity to the parasite Ags:
CMI to parasite Ag can also cause sever tissue damage for e.g: in
Schistosomiasis portal fibrosis and pulmonary hypertension are
probably, due to cellular response to Schistosoma eggs deposited in
tissue and granulomatous lesions occur against Schistosoma ova or
dead and degerated parasites.

Lecture over
Thanks for Attention

Immunopathology

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