Auto immunity and immunodeficiencies

1. Autoimmunity

2. Autoimmunity
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▰ Condition in which the body’s own immunologically competent cells or
antibodies (auto antibodies) act against its self-antigens resulting in structural
or functional tissue damage or disease.
▰ Paul Ehrlich had first introduced the concept of autoimmunity; he termed this
condition as “horror autotoxicus”.
▰ Normally immune system does not react to its own antigens due to a protective
mechanism called tolerance.
▰ Any breach in tolerance mechanisms predispose to several autoimmune
diseases.

3. IMMUNOLOGICAL TOLERANCE
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▰ Several innate mechanisms protect the body’s cells from destruction by its own
immune cells. This is referred to as Tolereance
▰ Mediated by two broad mechanisms:
 Central tolerance- it deletes T and B cell clones during their maturation in
central lymphoid organs (i.e., in the thymus for T cells and in the bone marrow
for B cells). If they have any self- antigen- recognizing receptors
 Peripheral tolerance:- Back-up mechanisms that occur in the secondary
lymphoid organs to render those cells inactive which escape central tolerance.

4. Mechanisms of Auto immunity
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1. Antigenic alteration- some cells undergo alteration in their antigens due to chemical,
physical (Irradiation, Photosensitivity and cold allergy) and biological (bacterial enzymes)
influences or by mutation . Such altered antigens or neoantigens, may mount an immune
response
Examples: Neuraminidases formed by myxo viruses and several bacterial act on erythrocytes and
release the T antigen.
2. Sequestered antigens- certain self antigens (example lens antigen of eye and sperm antigen
of spermatozoa) are present in closed system during fetal life and not accessible to the
immune apparatus. These are known as Sequestered antigens.
a. lens antigen is enclosed in capsule. If injured, antigen leaks and induces immune response causing
damage to other eye
b. Spermatozoa develop only in puberty and are not recognized as self antigens. The mumps virus
damages the basement membrane of seminiferous tubule leading to leakage of sperms and initiation of
an immune response resulting in orchitis

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Some antigens are hidden below the surface and hence not exposed to the immune system. However following tissue
damage they are exposed to the immune system and mount an immune response. This is called epitope spreading
3. Cross reacting Foreign antigens – organ-specific antigen are present in several species. The injection of heterologus
organ –specific antigens may mount an immune response and cause damage to the host
Examples:
a. Anti-rabies neural vaccine is prepared from infected sheep brain tissue. On injection, there is cross reaction
between human and sheep brain antigens and person mounts immune response
b. Some M proteins are present on Streptococci and human heart muscle therefore repeated streptococcal infection
will mount an immune response which can damage the heart.
c. Some streptococcal antigens are also found on human renal glomeruli. Infection with such nephritogenic
streptococcal strains may lead to glomerulinephritis in man due to antigenic sharing.
4. Molecular Mimicry-
Some microorganisms share antigenic determinants (epitopes) with self-antigens.
Immune response against such microbes would produce antibodies that can cross-react with self-antigen.
Example: Acute rheumatic fever and multiple sclerosis (molecular mimicry involving T-cell epitopes).

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5. Polyclonal B cell activation:- One antigen generally activates only its corresponding B
cells. However certain stimuli like (chemicals 2-mercaptoethanol, bacterial products Ex.
PPD and LPS) can non- specifically turn on multiple B Cell clone and form multiple non-
specific antibodies.
Example:- Mycoplasma, EBV, Malaria – auto-antibodies against RBC are formed.
Polyclonal T Cell activation: Super antigens released from microbes (e.g. Staphylococcus
aureus), polyclonally activate the T cells directly by binding to antigen non-specific Vβ
region of T cell receptors and cause Toxic shock syndrome (TSS)
6. Forbidden clones:- some immuno-competent cells are hidden. Sometimes the
immunological homeostasis mechanism breaks down leading to cessation of tolerance and
the emergence of immuno-competent cells capable of mounting immune response against
self antigens.
Example: Injection of self-antigen with Freund’s adjuvant will lead to auto immunization

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7. Altered T or B cell function- enhanced helper T cell (Th) and decreased
suppressor T cell (Ts) can cause auto immunity. This may be due to defect in
thymus, stem cell development and macrophage function.
8. Genetic factors such as defective Ir or Immunoglobulin genes can also
cause autoimmunity

8. Common features of autoimmune diseases
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1. Genetic Pre-disposition
2. Higher incidence among females
3. More than one type of auto immune lesion occurs in one individual
4. Chronicity and usually non-reversible
5. Deposition of immunoglobulin's at site of lesion such as renal glomeruli
6. Accumulation of lymphocytes and plasma cells at site of lesion
7. Demonstrable auto-antibodies
8. Elevated levels of immunoglobulins
9. Benefit from corticosteroid or other immunosuppressive therapy

9. Autoimmune diseases and immune response produced with their clinical manifestations
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Single Organ or Cell Type Autoimmune Diseases
Disease Self-antigen present on Type of immune response & Important features
Autoimmune anemias
Autoimmune
hemolytic anemia
RBC membrane proteins Auto-antibodies to RBC antigens triggers
complement mediated lysis or antibody-mediated
opsonization of the RBCs
Drug induced
hemolytic anemia
Drugs alter the red cell
membrane antigens
Drugs such as penicillin or methyldopa interact with
RBCs so that the cells become antigenic
Pernicious anemia Intrinsic factor (a membrane-
bound protein on gastric parietal
cells)
Auto-antibodies to intrinsic factor block the uptake of
vitamin B 12; leads to megaloblastic anemia

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Single Organ or Cell Type Autoimmune Diseases
Disease Self-antigen present on Type of immune response & Important features
Myasthenia gravis Acetylcholine receptors Blocking type of auto-antibody directed against Ach receptors
present on motor nerve endings, leads to progressive
weakening of the skeletal muscles
Graves’ disease Thyroid-stimulating hormone
(TSH) receptor
Anti TSH- auto-antibody (stimulates thyroid follicles, leads to
hyperthyroid state)
Post-streptococcal
glomerulonephritis
Kidney Streptococcal antigen- antibody complexes are deposited on
glomerular basement membrane
Hashimoto’s thyroiditis Thyroid proteins and cells Auto-antibodies and TDTH cells targeted against thyroid antigen
leads to suppression of thyroid gland.
 Seen in middle aged females
 Hypothyroid state is produced (↓ production of thyroid
hormones)

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Systemic Autoimmune Diseases
Disease Self-antigen present on Type of immune response & Important features
Systemic lupus
erythematosus
Auto-antibodies are produced
against various tissue antigens such
as DNA, nuclear protein, RBC and
platelet membranes.
 Age & sex- Women (20-40 years of age) are commonly
affected; female to male ratio is-10:1.
 Immune complexes (self Ag- auto Ab) are formed;
which are deposited in various organs
 Major symptoms- Fever, butterfly rash over the
cheeks, arthritis, pleurisy, and kidney dysfunction
Rheumatoid
arthritis
Here, a group of auto-antibodies
against the host IgG antibodies are
produced called RA factor. It is an
IgM antibody directed against the
Fc region of IgG.
ACPA (Anti citrullinated peptide
antibodies) are also produced
 Age & sex- Women (40-60 years of age) affected
 Auto-antibodies bind to circulating IgG, forming IgM-
IgG complexes that are deposited in the joints and can
activate the complement cascade.
 Major symptoms-
Main feature-Arthritis (chronic inflammation of the joints,
begins at synovium; most common joints involved are-
small joints of the hands, feet and cervical spine)
Other features-hematologic, cardiovascular, and
respiratory systems are also frequently affected

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Systemic Autoimmune Diseases
Disease Self-antigen present on Type of immune response & Important features
Scleroderma
(Systemic Sclerosis)
Nuclear antigens such as DNA
topoisomerase and centromere
present in heart, lungs, GIT, kidney,
etc
Helper T cell (mainly) and auto-antibody mediated.
Excessive fibrosis of the skin, throughout the body
Two types-
1.Diffuse scleroderma- Auto-antibodies against DNA
topoisomerase I (anti-Scl 70) is elevated
2.Limited scleroderma- ↑Anticentromere antibody,
characterized by CREST syndrome-calcinosis, Raynaud
phenomenon, esophageal dysmotility, sclerodactyly, and
telangiectasia
Multiple sclerosis Brain (white matter) Self-reactive T cells produce characteristic inflammatory lesions
in brain that destroys the myelin sheath of nerve fibers; leads to
numerous neurologic dysfunctions

13. Laboratory Diagnosis of Autoimmune Diseases
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1. RA factor (by latex agglutination test)- RA factor is an IgM autoantibody
directed against Fc portion of IgG, good sensitivity. False positive - seen in
other autoimmune diseases
2. Autoimmune hemolytic anemia: Diagnosed by Coombs test
Anti-Sm (smith) antibodies
Anti-double stranded DNA (dsDNA): Highly specific, used for confirmation of cases

14. Laboratory Diagnosis of Autoimmune Diseases
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The main principle – capture of auto-antibodies from serum using immobilized auto
antigens derived from cells
1. Indirect Immunofluorescence- to detect antibodies against antinuclear antigens
namely ANA
2. Direct immunofluorescence test -Lupus band test- detect deposits of
immunoglobulins and complement proteins in the patient's skin
3. Enzyme immunoassay- to detect the presence of auto-antibodies or auto-
antigens in biological fluids.
4. Multiplex immunoassay- simultaneous detection of different auto antibodies
against a large number of antigens.
5. Anti CCP (Cyclic Citrullinated peptide) ELISA- detects human auto- antibodies
against CCP (which is a circular peptide containing the aminoacid citrulline)
predicts the development of RA in future

15. Immunodeficiency Disorders

16. DEFINITION AND CLASSIFICATION
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▰ Immunodeficiency - state where the defence mechanisms of the body are
impaired, leading to enhanced susceptibility to microbial infections as well as
to certain forms of cancer.
▰ Immunodeficiency diseases are broadly classified as:
 Primary immunodeficiency – due to abnormalities in development of
immune system
 Secondary immunodeficiency- due to diseases, drug, nutritional
deficiencies which interfere with proper functioning of the mature
immune system

17. Classification of primary immunodeficiency diseases
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Humoral immunodeficiency (B cell defects)
 Bruton disease (X-linked agammaglobulinemia)
 Common variable immunodeficiency
 Isolated IgA deficiency
 Hyper-IgM syndrome
Cellular immunodeficiencies (T cell defects)
 DiGeorge syndrome (thymic hypoplasia)
 Chronic mucocutaneous candidiasis
 Purine nucleoside phosphorylase (PNP) deficiency
Disorders of complement
 Complement component deficiencies
 Complement regulatory protein deficiencies

18. Classification of primary immunodeficiency diseases (Cont..)
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Combined immunodeficiencies (B and T cell defects)
 Severe combined immunodeficiencies
• Cytokine receptor mutation
• Adenosine deaminase (ADA) deficiency
 Wiskott–Aldrich syndrome
 Ataxia telangiectasia
 Nezelof syndrome
Disorders of phagocytosis
 Chronic granulomatous disease
 Myeloperoxidase deficiency
 Chediak–Higashi syndrome
 Leukocyte adhesion deficiency
 Lazy leukocyte syndrome
 Job’s syndrome or Hyper-IgE syndrome

19. Essentials of Medical Microbiology by Apurba S Sastry © Jaypee Brothers Medical Publishers
Examples of Infections in Immunodeficiencies
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Pathogen Type T-Cell Defect B-Cell Defect Granulocyte Defect Complement Defect
Bacteria Bacterial sepsis Streptococci,
Staphylococci,
Haemophilus influenzae
Staphylococci,
Pseudomonas
Nocardia
Neisseria,
Other pyogenic
infections
Viruses Cytomegalovirus,
Epstein-Barr virus,
Severe varicella,
Chronic infections with
respiratory and intestinal
viruses
Enterovirus encephalitis -
Fungi Candida,
Pneumocystis jirovecii
- Candida,
Aspergillus

20. Examples of Infections in Immunodeficiencies (Cont..)
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Pathogen Type T-Cell Defect B-Cell Defect Granulocyte Defect Complement Defect
Parasites - Giardiasis - Neisseria,
Other pyogenic
infections
Special features Aggressive disease with
opportunistic pathogens,
failure to clear infections
Recurrent
sinopulmonary
infections,
Sepsis, chronic
meningitis
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21. Lab diagnosis of Immuno deficiency
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1. B cells defect detection by Flow Cytometry – Humoral immunodeficiency is detected
by estimating the B cells that may be absent in certain immune disorders associated
with antibodies .
2. T cell defect detection by CBC count and differential count
3. Severe combined immuno deficiency(SCID) done by mutation analysis (most
accurate)
4. Complement deficiency detect done by Total hemolytic complement- assay (CH 50)
5. Complete blood count (CBC)-
a. peripheral blood smear - Netropenia, Lymphopenia, Leucocytosis, Thrombocytopenia
b. quantitative serum Ig levels
c. Ig M antibody
d. Ig G antibody
e. Phagocytic cell deficiency measured by Flow cytometry, Nitroblue tetrazolium test
(NBT)