IMMUNOLOGY (PATHOLOGY +MICROBIOLOGY) REVISION NOTES

21-04-2018
Immunology
TONY SCARIA 2010
KMC
Infections
TONY SCARIA 2010
KMC

21-04-2018
• Cross infection
• In a patient already suffering from a disease a new infection is set up from
another host
• Nosocomial infection
• Hospital acquired cross infection
• Iatrogenic infections
• Physician induced infections resulting from investigative therapeutic or other
procedure
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• Exaltation
• Increase in pathogenicity of organism
• Attenuation
• Decrease in virulence of strain  used as vaccine
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• Bacteremia
• Minute amount bacteria in blood while brushing straining @ sttol
• Removed by macrophages
• Septicemia
• Bacteria multiply to produce toxic products
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• Endemic
• Continuously present in an area
• Constantly present
• Epidemic
• Large population in particular locality
• Pandemic
• Epidemic involving different areas of globe
TONY SCARIA 2010
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TONY SCARIA 2010
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Immune system
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Ratio of CD4: CD8 =
2:1
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T cell
• Arise from bone marrow also in yolk sac & liver before birth
• Maturity of T cell takes place in thymus
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B cell
• Originate as well as mature in bonemarrow
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• Pan B Cell marker  CD 19
• Pan T cell marker  CD3
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Th17
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Th17
TONY SCARIA 2010
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Clonal selection
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TCR
• 2 types
• 95 % αβ
• 5 % δγ
• Signal transduction
molecule  CD3 & ζ
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T cell co receptors
• On helper cells CD4 cells
• On cytotoxic cells CD8
cells
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Costimulatory signal
• Interacts with CD28 of B7 –1 or B7 -2
expressed on APC
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Anergy
• Permanent inactivation of T cell
due to lack co stimulatory
signal
• Protective mechanism to
prevent activation of T cells
against self Ag (peripheral
immunological tolerance )
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• Absence of costimulation leads to anergy d/t lack of production of IL2
IL4 & IFN γ
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EBV (Epstein barr virus recognises CD 21 of B
cells)
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Lymphocytes
B cell
• Humoral immunity
• Produced in germinal centres of
LN & spleen
• 12 % lymphocytes
• Hypersensitivity type 1,2 & 3
T cell
• Cell mediated immunity
• Produced in paracortical redions
of LN & spleen
• 75 % lymphocytes
• Type 4 hypersensitivity
TONY SCARIA 2010
KMC
b cell
• Maturation in bonemarrow
• On surface of B cell  Ab
• Responds directly to antigen
• Clonal selection in to plasma
cells (produce Ab) and memory
cells
T cell
• Maturation occurs in thymus
• T cell receptors are present
• Antigen + MHC of antigen
presenting cell (b cell + dendritc
cell)
• T helper cells (produce
cytokine)+ cytotoxic t hlper cells
(killer cells) + memory cellsTONY SCARIA 2010
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SRBC  sheep red blood cells agglutinate
around  t lymphocyte
SRBC receptor  measles receptor
CD2
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EAC rosette (C3 receptor) in b lymphocyte
TONY SCARIA 2010
KMC
Blast transformation
• In T lymphocytes
• Phytohaemagglutinin
• Conconavalin A
• Anti CD3
• In B lymphocytes
• Bacterial endotoxin
• Anti ig
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KMC

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B cells are having numerous microvilli on their
surface
TONY SCARIA 2010
KMC
In lymph node
T cell
• Paracortical area
B cell
• Germinal centres
• Cortical follilces
• Medullary cord
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TONY SCARIA 2010 KMC
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Cytotoxic T cells
CD 8 which recognises MHC class I
(1*8=8)
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Cytotoxic T cells
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Mechanism of killing y cytotoxic t cells
• Perforin & granzyme killing
• Perforin forms pores allows entry in
to granzyme
• Fas/FasL mediated apoptosis
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Cytotoxic cells kill virus infected,neoplastic
and donor graft cells
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Releases perforin granzyme and granulosin
granulosin
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T cell subset ratio CD4:CD8=2:1
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Helper T cells master egulatory cells
CD4 which recognises MHC class II (2*4=8)
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Helper t cells
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IL -4,5 and 6
IL2 IFN
gamma
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Suppressor t cells
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Regulatory t cells
• Regulate the activity of Th and
Ts
• activation of transcription factor
FOXP3
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B lymphocytes
• B cell also can present Ag to T
helper cell by BCR
• It is also having a co
stimulatory signal b/w CD 40
& CD 40 L
TONY SCARIA 2010
KMC
• B cell receptor complex
contains a membrane
bound IgM or IgD&
associated signalling
Igα(CD79a) & Igβ(CD79b)
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Lack of costimulatory signal Anergy
• Permanent inactivation
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BCR vs TCR
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IgM & IgD receptors present on mature &
naïve B cell
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IgM or IgD present on b cell receptor
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Null cells aka Large granular lymphocyte
• Contain large azurophilic granules
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Null killer cells
• Lack surface markers of both B & T Cells
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ADCC
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• – Receptor for Fc portion of IgG (CD-16) which is used for ADCC
(antibody dependent cell mediated cytotoxicity).
• – Receptor for NCAM-I (CD 56).
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Neutreophils
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• Lifecycle of N phils is 4 – 8 hrs in circulation another 2-5 days in tissue
• Major cells in ac inflammation
• polymorphonuclear
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• Primary (azurophilic granules)granule
• Promyelocytic stage
• More destructive
• Secondary granules
• Myelocytic stage
• Less destructive
• Contain lactoferrin
• Tertiary granules
• During chemotaxis
• Contain gelatinase & hydrolaseTONY SCARIA 2010
KMC
Monocyte / macrophages
• Dominant cellular player in c/c inflammation
• Arise from monoblast in marrow  released as monocytes & migrate
tissue & form macrophages
• Lifespan of monocytes is 1-3 days whereas tissue macrophages have
lifespan of 3months – years
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• Lung  alveolar macrophages
• Brain  microglia
• Skin  Langerhans cells
• Connective tissue  histiocytes
• Bone  osteoclasts
• Liver Kupffer cells
• Placenta  hoffbauer cells
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Classically activated
• Activated Microbial products &
IFNγ
• Microbicidal & pathogenic
inflammation
Alternately activated
• Activated by microbial products
& IL 4 / IL5
• Antiinflammatory actions &
wound repair
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Eosinophils
• In allergic responses & parasitic infestation
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Eotaxin acts as major chemokine
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Mast cell & basophil
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• Basophils are seen in blood
• Mast cells in tissues
• Important cells in in immediate hypersensitivity
• Important source of histamine
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Antigen presenting cells
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APC express both MHC class I & Class II
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Dendritic cells
• Follicular dendritic cells  presents to B cells
• Dendritic cells  presents to T cells
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KMC
B cell act as APC
Uptake of Ag by BCR
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HLA
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MHC is located on chromosome 6
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MHC
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• mhc is absent in in RBC
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MHC I MHC II
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MHC class I against endogenous Ag MHc class
II Ag against exogenous Ag
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HLA on short arm of chromosome 6 (p)
MHC
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HLA D
• Most important for organ transplantation
• HLA order of importance before organ transplantation
• HLA DR >B >A
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HLA B27 associations
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MHC class I restriction
• Graft rejection
• Cytotoxic cell mediated cytolysis
of viral infected or tumour cells
MHC CLASS II RESTRICTION
• Graft vs host reaction
• Mixed leucocyte reactionn
TONY SCARIA 2010
KMC
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Cluster differentiation marker
• Primary stem cell &
progenitor cell associated 
CD 34
• Pan T cell marker  CD3
• Pan B cell matrker  CD19
• NK cell  CD 16 CD56
TONY SCARIA 2010
KMC
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CD 45 is called leucocyte common Ag
• CD45 RO  memory cells
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• CD95 is a death receptor
• Marker for apoptosis
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Cytokines
• Soluble polypeptides
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IL4  Ig class switching
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IL 5
It promotes the growth and differentiation of B cells and
eosinophils. It enhances the synthesis of IgA and also stimulates
the production and activation of eosinophils
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KMC
• IL-13 is produced by Th-2 cells.
• It is associated with pathogenesis of allergic airway disease (asthma). It is
involved in the occurrence of hyper-responsiveness seen in asthma.
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TONY SCARIA 2010
KMC
Chemokines
• Classified on the basis of
conserved cysteine residues
• CXC chemokines
• Acts on neutrophils
• IL 8 TNF
• CC chemokines
• Attracts all leukocytes except
neutrophil
• eotaxin
• C chemokines
• Act on lymphocytes
• Lymphotactinn
• CXXXC chemokines
• Act on lymphocytes & monocytes
• Fructalkine
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Interferon
• Glycoproteins produced by virus infected cells (host coded proteins)
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Interferon
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• INTERFERON
• On exposure to interferon cells prdoduce a protein (translation inhibiting
protein) which inhibit translation of mRNA
• Species specific
• Action is not virus specific
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KMC
CRP
• Nonspecific inflammatory acute
phase protein
• Beta globulin
• Produced in liver
• Testing is done by passive latex
agglutination test precipitates with
somatic C antigen of pneumococci (but
it is not an antibody)
• Binds to phosphorylcholine of
microorganism activate compliment
system TONY SCARIA 2010
KMC

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Immunity
TONY SCARIA 2010
KMC
• Natural / innate immunity
• By virtue of genetic and
constitutional make up
• Nonspecific
• No memory
• Acquired immunity
• Acquired during life
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Components of natural immunity
• Epithelial barriers
• Macrophages
• Dendritic cells
• Natural killer cells
• Plasma proteins : alternate pathway of complent system, CRP
• Pattern recognition receptors
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Pattern recognition receptors
• Part of innate immunity
•
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• Active immunity
• After exposure to foreign Ag
• Memory +
• Lag time +
• Negative phase +
• Passive immunity
• Preformed Ab are transferred, IgA in breast milk
• Rapid onset
• Lasts for Short span of time
• Adoptive immunity / transfer factor
• Transfer of immunocompetent cells (lymphocytes) transfer of active and passive
immunity TONY SCARIA 2010
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Herd immunity
• overall level of immunity in a community
• Eradication of an infectious disease depends on the development of a high
level of herd immunity against the pathogen
• When it is low  chance of epidemic+
• Eg :
• diphtheria,
• polio OPV
• Pertussis
• Measles, Mumps, Rubella
• Small Pox. TONY SCARIA 2010
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Local immunity
• The immunity at a particular site, generally at the site of invasion and
multiplication of a pathogen
• Local immunity is conferred by secretory IgA antibodies in various
body secretions.
• These antibodies are produced locally by plasma cells present on
mucosal surfaces or in secretory glands.
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Antigen
• Stimulates production of antibody (IMMUNOGENICITY)
• with which it reacts specifically and in an observable manner
(IMMUNOREACTIVITY)
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• Determinants of Antigenicity
• – Molecular size (<5000 are non-antigenic)
• – Chemical nature (usually protein and polysaccharide)
• – Susceptibility to tissue enzymes
• – Foreignness
• – Antigen specificity
• – Species specificity
• – Isospecificity
• – Autospecificity (except lens protein and sperm)
• – Organ specificity TONY SCARIA 2010
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Hapten(incomplete Ag)
• Incapable of inducing antibody formation (ABSENT
IMMUNOGENICITY)
• Reacts specifically with the Ab
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• Simple haptens combine with specific antibody but do not produce
any antigen-antibody product viz precipitation.
• No precipitation
• Complex haptens do combine with specific antibody to produce
precipitates because of presence of multiple antibody combining sites
on its surface.
• Precipitation
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Epitope
• Smallest unit of antigenicity
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Paratope
• It is combining area of the antibody molecule, corresponding to the
epitope
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Idiotope
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• The idiotype is the specific region of the Fab part of the antibody
which binds to the antigen and this located at the amino terminal of
the L chains and the H chains.
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Premunition
• Resistance to superinfection
• Immunity to reinfection lasts only as long as the original infection
remains active
• In syphilis
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Heterophile or heterogenic specificity
• Same or closely related Ag occurs
• Forssman antigen
• In man, animal,birds,plants
• Weil- felix reaction
• Shared by certain strains of proteus (OX19,OX2 and OXK)
• Paul bunnel test
• Epstein barr virus antigens share antigens of ox RBC
• Cold agglutination test
• Mycoplasma antigens with human O RBCTONY SCARIA 2010
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Superantigens
• staphylococcal enterotoxins,toxic shock syndrome toxin, exfoliative
toxins, and also some viral proteins
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Activates large number of T cells irrespective
of their antigenicity
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Super antigens stimulate T lymphocytes-
produces
• TNFα
• IL-1β
• IL-2
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• Lateral portion of α chain of class II MHC & β
portion of TCR
• Superantigen are capable of activating uto 20 %
peripheral T cell pool
• Conventional T cell stimulation only 1 in 10000
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Antigen presentation is not required for super
Ag
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heterophile antigens
• The same or closely related antigens, sometimes present in tissues of
different biological species, classes, or kingdoms are known as
heterophile antigens
• Weil–Felix reaction, Paul-Bunnell test, and cold agglutination tests
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Sequestrated antigens
• cryptoAg
• Hidden antigen
• Antigens which are not exposed to immune system during embryonic
life
• Hence if released it can cause immune response
• Sequestration in time
• Sperms (absent in embryonic life produced at puberty)
• Sequestration in space
• Lens proteins CNS proteinsTONY SCARIA 2010
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Antibody
• Form part of gamma globulin fraction
• Synthesised by plasma cells
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2 light and 2 heavy
chain
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Papain results in 2 Fab + 1 Fc
Pepsin results F(ab)2 + Fc
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Light chain
• Light chain - λ(40%) or κ (60%)
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L & H chains are divided in to variable and
constat regions
• Variable region antigen binding
• Hypervariable region  complementary
determining site
• Constant region  biological function
TONY SCARIA 2010
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Antibody
TONY SCARIA 2010
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Amino terminal is concerned with binding to
antigen
Carboxy terminal for compliment
fixationTONY SCARIA 2010
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• Hypervariable region is towards NH2 terminal  antigen binding sites
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Based on heavy chain
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Ig G
• Most abundant Ig
• Longest t1/2
• Secondary immune response
• Distributed in intravascular & extravascular compartment
• Only Ig G can cross placenta (Ig 1,3 and 4)
• Major protective Ig in neonate
• antiD Rh incompatibility
• Activates compliment via classical pathway (IgG 3***)
• Opsonises bacteria (Ig G 1 and 3 )
• Ig G 2  against polysaccharide Ag (encapsulated bacteria)
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Ig A
• Two types
• Secretory
• Produced by plasma cells (highest in jejunum)
• Principal Ig in secretions (respiratory & GI tract)
• Protects mucosal surfaces
• Dimeric forms joined by J chain (synthesised by epithelial cells)
• Secretory component (synthesised by epithelial cells)
• Ig A Alternate pathway
• Helps in local immunity of gut
• Serum (monomer)
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Ig M
• Macroglobulin made of 5 monomeric Ig G units
• Massive , massive molecular weight
• Mainly intravascular
• Primary immune response
• First Ab to appear @ 20 weeks of intrauterine life
• Ig M Ab  in fetus or newborn
• Congenital syphilis,rubella,toxoplasma
• Blood group Ab (isohaemagglutinin) Ig M
• Anti A Anti B
• Maxim sedimentation coefficient
• Activates complement via classical pathwayTONY SCARIA 2010
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• Theroretical valency of IgM is 10 is seen only in haptens with larger
antigens valency of IgM is 5 d/t steric hindrance
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Ig D
• Antigen receptor on surface of B lymphocyte
• Contains Delta heavy chain
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Ig E
• Maximum carbohydrate content
• Prausnitz kustner reaction
• IgE binds to mast cells
• Elevated in atopic conditions
• Against helminthic parasites
• Type 1 hypersensitivity
• Heat labile
• Homocytotropism
• IgE of humans can bind with human cells only
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• Classical pathway
• Activated by Ig M and I g G (IgM > IgG3 > IgG1 > IgG2 )
• Alternate pathway
• Activated by Ig A
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• Serum concentration, Half life in days, Daily production (mg/kg)
• G > A > M > D > E
• Present in milk
• Ig A & Ig G
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Isotype switching
• Constant region portion
of Ab heavy chain is
changed
• Variable region remains
same
• Induced by IFN γ & IL4
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Abnormal immunoglobulins
• Benz jones proteins
• Multiple myeloma
• Light chains of Ig
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• Waldenstrom’s macroglobulinemia
• Hyperviscosity syndrome
• IgM
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• Heavy chain disease
• Over production Fc portion of Ig
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Abnormal immunoglobulin
• Cryoglobulinemia
• Most cryoglobulins consist of either IgG or IgM or their mixed precipitates.
• In cryoglobulinemia, serum from patient precipitates on cooling and
redissolves on warming
• Associated with macroglobulinemia ,myelomas & auto immune disease
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• T cell independent activation
• Directly stimulate B cell with out processing by antigen presenting cell
• Poly clonal B cell activation
• No memory
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• Chemical nature & immunogenicity
• Proteins>> polysaccharides >>lipids & nucleic acid
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Protein antigen
• T cell dependant
• More immunogenic
• Memory +
Carbohydrate Ag
• T cell independent
• Less immunogenic
• No memory
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Adjuvants
• Adjuvants are the substances that when mixed with an antigen and
injected with it boost the immunogenicity of the antigen.
• Adjuvants increase both the strength and the duration of immune
response
• Aluminium hydroxide & aluminium phosphate
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Antigen – antibody reaction
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Ag Ab reaction
• specific
• No denaturaatin of Ag or Ab
• Combination occurs at surface
• Combines in varying proportions
• No covalent bonds
• Hydrogen bonds / ionic / van der waals bonds are involved
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Ag-Ab reaction
• stages:
• Primary
• rapid and reversible,
• without any visible effects
• ionic bonds, hydrogen bonds, van der Waals forces, and hydrophobic interactions
• Secondary
• irreversible interaction between antigen and antibody
• Visible reactions +
• Covalent binding
• Tertiary
• Neutralisation and removal of tissue or pathogen
• Eg humoral immunity , allergyTONY SCARIA 2010
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Secondary stage
• In most but not all primary stage followed by secondary one.
• Leads to demonstrable (visible) effects -------
* Precipitation.
* Agglutination.
* Lysis of cell.
* Killing of live antigens.
* Neutralisation of toxins.
* Complement fixation.
* Immobilisation of motile organisms.
* Enhancement of phagocytosis.TONY SCARIA 2010
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Precipitation reaction
Soluble Antigen
+ Antibody
suitable temperature and pH
insoluble precipitate / ﬂoccules
Flocculation  soluble antigen reacts with antibody not
precipitated remain suspended
Eg : VDRL  slide flocculation testTONY SCARIA 2010
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Precipitation reaction
Prozone phenomena or antibody excess occurs in:
– Enteric fever (Salmonella Typhi)
– Brucellosis
– Leptospirosis
– Syphilis
Post zone phenomena (Antigen excess) occurs in -
– Cryptococcus
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Precipitation reaction is used to detect Ag
less sensitive for detection of Ab
• Ring test
• – Ascoli thermo precipitation test ( anthrax),
• – Lancefeld grouping (Streptococcus).
• Slide ﬂocculation test – VDRL, RPR
• Tube ﬂocculation test – Kahn test, standardization of toxin
• Immuno-diffusion (In gel):
• – Produces visible band, so interpretation is easy
• – Can be preserved
• – Differentiate between antigensTONY SCARIA 2010
KMC

21-04-2018
Examples of immunodiffusion in gel
• – Single diffusion in one dimension (Oudin procedure)
• – Double diffusion in one dimension (Oakley Fulthorpe procedure)
• – Single diffusion in two dimension (Radial immunodiffusion)
• – Double diffusion in two dimension – e.g. include Elek gel
precipitation(C.diphtheriae toxigenicity testing), and Eiken test (E.coli)
TONY SCARIA 2010
KMC
TONY SCARIA 2010
KMC

21-04-2018
Single diffusion in two dimension (Radial
immunodiffusion)
TONY SCARIA 2010
KMC
Double diffusion in two dimension
TONY SCARIA 2010
KMC

21-04-2018
5. Immunoelectrophoresis
• Graber & Williams devised this technique.
• This involves the electrophoretic separation of
composite Ag into its constituent proteins, followed
by immunodiffusion against its antiserum – separate
precipitin lines.
• It is performed on an agarose gel with an Ag well &
Ab trough cut on it.
• The test serum is placed in the antigen well &
electrophoresed for about 1 hour.
• Ab against human serum is placed in the trough &
diffusion allowed for 18 – 24 hrs.
TONY SCARIA 2010
KMC
TONY SCARIA 2010
KMC

21-04-2018
ELECTROIMMUNODIFFUSION
• The development of precipitin lines can be
speeded up by electrically driving the Ag & Ab.
• Two types
1. Counterimmunoelectrophoresis (One dimensional
double electroimmunodiffusion)
2. Rocket electrophoresis (One dimensional single
electroimmunodiffusion)
TONY SCARIA 2010
KMC
1. Counterimmunoelectrophoresis (CIE)
• This involves simultaneous electrophoresis of Ag & Ab
in gel in opposite directions resulting in precipitation at
a point between them.
• Produce precipitation lines within 30 mins.
• Clinical application: detecting Ags like alphafetoprotein
in serum, Ags of Cryptococcus & Meningococcus in the
CSF.
TONY SCARIA 2010
KMC

21-04-2018
2. Rocket electrophoresis
• Used for quantitative estimation of Ags.
• The antiserum to the Ag to be quantitated is
incorporated in agarose gel on a slide.
• Ag in increasing concentrations, is placed in wells
punched in the set gel.
• The Ag is electrophoresed into the Ab containing
agarose.
• The pattern of immunoprecipitation resembles a
ROCKET.
TONY SCARIA 2010
KMC
Rocket electrophoresis
ROCKET ELECTROPHORESIS IS USED TO QUANTIFY ANTIGENS
TONY SCARIA 2010
KMC

21-04-2018
Laurell’s two dimensional electrophoresis
• Variant of rocket electrophoresis.
• The Ag mixture is electrophoretically separated in a
direction perpendicular to that of the final rocket
stage.
• Used to quantitate each of the several Ags in a
mixture.
TONY SCARIA 2010
KMC
Agglutination
Insoluble Antigen + Antibody clumps
formation
suitable temperature and pH leads
More sensitive for detection of Ab than
precipitation
TONY SCARIA 2010
KMC

21-04-2018
Examples
• Slide agglutination
• Blood grouping & cross matching
• Tube agglutination test
• Widal test – Enteric fever
• Paul bunnel test
• Standard agglutination test – Brucella
• Microscopic agglutination test – Leptospira
• Weil felix – Rickettsia
• Paul Bunnel test-– EBV
• Blood grouping (slide agglutination)
• Coombs test for incomplete (IgG) AbTONY SCARIA 2010
KMC
Passive agglutination
• Passive agglutination employs carrier
particles (latex)hat are coated with
soluble antigens.
• This is usually done to convert
precipitation reactions into
agglutination reactions, since the latter
are easier to perform and interpret and
are more sensitive than precipitation
reactions for detection of antibodies.
• Rose waaler test for RA (haemagglutination)
• Detection of ASO CRP HCG
TONY SCARIA 2010
KMC

21-04-2018
Reverse passive agglutination to detect Ab
TONY SCARIA 2010
KMC
TONY SCARIA 2010
KMC

21-04-2018
TONY SCARIA 2010
KMC
• DIRECT COOMB TEST
• AIHA
• Detect IgG attached to
RBC (fetal RBC in HDN)
• INDIRECT COOMB TEST
• Maternal serum in HDN
• Detect IgG
TONY SCARIA 2010
KMC

21-04-2018
Compliment fixation
TONY SCARIA 2010
KMC
TONY SCARIA 2010
KMC

21-04-2018
If patient serum has antibody-
complements are utilized in the 1st
step, so not available for the 2nd
step, hence there is no hemolysis of
sheep RBC.
If patient serum has no antibody-
complements are not utilized in the
1st step, so available for the 2nd step,
hence there is complement mediated
hemolysis of sheep RBC
TONY SCARIA 2010
KMC
• Examples
• – Wasserman test (Syphilis)
TONY SCARIA 2010
KMC

21-04-2018
neutralization test
• – Schick test- Diphtheria toxin
• – Naegler reaction
• – Streptolysin O neutralization test
• Ab neutralises biological effects of virus, toxin and enzyme
• Viral neutralization test
• Bacteriophage neutralization test - By Plaque inhibition test.
TONY SCARIA 2010
KMC
• ELISA (Enzyme linked immunosorbent assay)- Enzyme tagged
• RIA (Radioimmuno assay) – Radioactive isotope lebelled
• Hormones
• tumour markers
• IFA (Immunoﬂouroscence assay) – Flouroscent dye lebelled
TONY SCARIA 2010
KMC

21-04-2018
Compliment system
TONY SCARIA 2010
KMC
• Complement activation takes place through any of the following three
pathways:
• 1. The classical pathway
• 2. The alternative pathway
• 3. The lectin pathway
TONY SCARIA 2010
KMC

21-04-2018
• ■ Immunoglobulins IgM and IgG
• IgM >IgG3 >IgG1 > IgG2> IgG4
• ■ Staphylococcal protein A,
• ■ C-reactive protein, and
• ■ DNA
TONY SCARIA 2010
KMC
TONY SCARIA 2010
KMC

21-04-2018
TONY SCARIA 2010
KMC
Alternate pathway
• Activators of the alternative pathway of complement activation
include
• (a) IgA,
• (b) IgD,
• (c) bacterial endotoxin,
• (d) cobra venom factor, and
• (e) nephritic factor
TONY SCARIA 2010
KMC

21-04-2018
Alternate pathway
TONY SCARIA 2010
KMC
Alternate pathway
TONY SCARIA 2010
KMC

21-04-2018
TONY SCARIA 2010
KMC
Membrane attack complex
TONY SCARIA 2010
KMC

21-04-2018
C3a C4a C5a acts as anaphylatoxins
TONY SCARIA 2010
KMC
Deficiency of c1 esterase inhibitor
• Hereditary angioedema
• Uncontrolled compliment activation
• ACE inhibitors are contra indicated
• Icatibant
• Bradykinin b2 receptor antagonist
• To treat acute hereditary angioedema
TONY SCARIA 2010
KMC

21-04-2018
C5b – c9 forms MAC
TONY SCARIA 2010
KMC
Deficiency of c5-c8(membrane attack
complex)
• Severe Neisseria infection,toxoplasmosis
TONY SCARIA 2010
KMC

21-04-2018
Deficiency of decay accelerating factor (DAF)
• Paroxysmal nocturnal hemoglobinuria
TONY SCARIA 2010
KMC
TONY SCARIA 2010
KMC

21-04-2018
TONY SCARIA 2010
KMC
• GPI anchored proteins
• Decay accelerating factor(CD55)  increases dissolution of c3 convertase
• Membrane Inhibitors of reactive lysis (CD59)  inhibit formation of M
TONY SCARIA 2010
KMC

21-04-2018
Deficiency of c3 and c3b inactivator
• Recurrent pyogenic bacterial infection
• Type III hypersensitivity reaction
TONY SCARIA 2010
KMC
C3b acts as an opsonin  helps in
phagocytosis
TONY SCARIA 2010
KMC

21-04-2018
IgM is most effective to fix compliment
TONY SCARIA 2010
KMC
TONY SCARIA 2010
KMC

21-04-2018
Hypersensitivity reactions
TONY SCARIA 2010
KMC
TONY SCARIA 2010
KMC

21-04-2018
Hypersensitivity reaction
Gell and coomb classification
TONY SCARIA 2010
KMC
Type 1 hypersensitivity
• Mediated by IgE
TONY SCARIA 2010
KMC

21-04-2018
Type 1 reaction
• Initial rapid early phase
• Late phase
TONY SCARIA 2010
KMC
TONY SCARIA 2010
KMC

21-04-2018
TONY SCARIA 2010
KMC
• Initial
TONY SCARIA 2010
KMC

21-04-2018
Type 1 hypersensitivity reaction
• Anaphylactic reaction
• Allergy ,atopy ,angioedema
• Hay fever
• Prausnitz kustner reaction
• Theobald smith phenomenon
• Schultz dale phenomenon
TONY SCARIA 2010
KMC
Casonis test  type 1
TONY SCARIA 2010
KMC

21-04-2018
Prausnitz kustner reaction  type 1
TONY SCARIA 2010
KMC
TONY SCARIA 2010
KMC

21-04-2018
Type II hypersensitivity
TONY SCARIA 2010
KMC
TONY SCARIA 2010
KMC

21-04-2018
TONY SCARIA 2010
KMC
Type II hypersensitivity
• Hemolytic anemia
• Transfusion reaction
• Erythroblastosis fetalis
• Myasthenia gravis
• ITP
• Rheumatic fever
TONY SCARIA 2010
KMC

21-04-2018
• Opsonization and phagocytosis.
• When circulating cells, such as erythrocytes or platelets, are coated (opsonized) with autoantibodies, with or without
complement proteins, the cells become targets for phagocytosis by neutrophils and macrophages . These phagocytes
express receptors for the Fc tails of IgG antibodies and for breakdown products of the C3 complement protein, and use these
receptors to bind and ingest opsonized particles. Opsonized cells are usually eliminated in the spleen, and this is why
splenectomy is of some benefit in autoimmune thrombocytopenia and hemolytic anemia.
• Inflammation.
• Antibodies bound to cellular or tissue antigens activate the complement system by the "classical" pathway. Products of
complement activation recruit neutrophils and monocytes, triggering inflammation in tissues, opsonize cells for
phagocytosis, and lyse cells, especially erythrocytes. Leukocytes may also be activated by engagement of Fc receptors, which
recognize the bound antibodies.
• Vascular rejection & vascular rejection in graft
• Antibody-mediated cellular dysfunction.
• In some cases, antibodies directed against cell surface receptors impair or dysregulate cellular function without causing cell
injury or inflammation . In myasthenia gravis, antibodies against acetylcholine receptors in the motor end plates of skeletal
muscles inhibit neuromuscular transmission, with resultant muscle weakness. Antibodies can also stimulate cell function
inappropriately. In Graves' disease, antibodies against the thyroid-stimulating hormone receptor stimulate thyroid epithelial
cells to secrete thyroid hormones, resulting in hyperthyroidism. Antibodies against hormones and other essential proteins
can neutralize and block the actions of these molecules, causing functional derangements.
TONY SCARIA 2010
KMC
Opsonization and phagocytosis.
TONY SCARIA 2010
KMC

21-04-2018
Antibody-mediated cellular dysfunction
TONY SCARIA 2010
KMC
TONY SCARIA 2010
KMC

21-04-2018
Type III hypersensitivity
• Immune complex deposited in post capillary venule  compliment
activation ↓compliment level in blood
TONY SCARIA 2010
KMC
• Ag Ab complex is mainly deposited in tissues where filtration occurs
• Kidney
• Synovium
• Lungs
• Blood vessels
TONY SCARIA 2010
KMC

21-04-2018
2 types
Arthus reaction, Farmer’s lung, Serum sickness, rheumatoid
arthritis,
necrotizing vasculitis, glomerulonephritis, SLE, immune
complex in
hepatitis B, and malaria
TONY SCARIA 2010
KMC
Serum sickness
• Occurs in 3 phases
• Immune complex formation
• Immune complex deposition
• Immune complex induced injury
• d/t compliment activation by deposited Ag Ab complexes
• Occurs after 10 days of Ag administration
TONY SCARIA 2010
KMC

21-04-2018
Arthus reaction
• deposition of antigen–antibody immune complexes activation of
complement  vascular occlusion and necrosis
• Hypersensitivity pneumonitis
• Farmer’s lung, cheese-washer’s lung, wood-worker’s lung, and wheat-miller’s lung are
the
• Shick test
• Intradermal injection of diphtheria toxin to test immunity status
TONY SCARIA 2010
KMC
Serum sickness
• systemic inflammatory reaction caused by deposition of immune
complexes at many sites of the body
• single injection acts as both priming and shocking doses
• Unlike type I
TONY SCARIA 2010
KMC

21-04-2018
Type 3 hypersensitivity
• Shick test
• reactive arthritis
• SLE
• Type 2 lepra reaction
• Glomerulonephritis
• Serum sickness
• Arthus reaction
• PAN TONY SCARIA 2010
KMC
Type IV hypersensitivity
• Delayed type
• Cell mediated
• DTH reactions are of two types:
• contact hypersensitivity and
• tuberculin-type hypersensitivity reactions
TONY SCARIA 2010
KMC

21-04-2018
TONY SCARIA 2010
KMC
Contact dermatitis  evoked by urushiol
(antigenic component of poison ivy )
TONY SCARIA 2010
KMC

21-04-2018
Type IV hypersensitivity
• Mantoux test
• Guillain barre syndrome
• Hashimotos thyroiditis
TONY SCARIA 2010
KMC
TONY SCARIA 2010
KMC

21-04-2018
TONY SCARIA 2010
KMC
Cutaneous hypersensitivity test
• Type I hypersensitivity
• Casonis test
• Type III hypersensitivity
• Shick test
• Type IV hypersensitivity
• Tuberculin test
• Lepromin test
TONY SCARIA 2010
KMC

21-04-2018
Type V hypersensitivity
• Stimulatory hypersensitivity (type 2 hypersensitivity)
• Ab recognise cell surface receptors  impairing cell signalling
• Graves ds
• Myasthenia gravis
TONY SCARIA 2010
KMC
shwartzman reaction
• Not an immune reaction
• Not a hypersensitivity
• Mainly bacterial endotoxin injection
• Initial intradermal preparatory dose followed by IV provocative dose
• Seen in
• Waterhouse friderichson syndrome
• Gram negative septic shock
• TSST
TONY SCARIA 2010
KMC

21-04-2018
Transplant reactions
TONY SCARIA 2010
KMC
Based on donor
• Aurograft  graft from self
• Isograft  graft from genetically identical person (identical twin)
• Allograft (homo/allogenic graft)genetically unrelated member of
same sps
• Xenograft  from different species
TONY SCARIA 2010
KMC

21-04-2018
2 types of reactions
• Host vs graft reaction
• Reaction of host to grafted organ ie graft rejection
• Graft vs host reaction
• Immune response of graft against antigens of host ie RUNT disease
TONY SCARIA 2010
KMC
Host vs graft ds (graft rejection)
• Most important Ag is HLA antigen of grafted tissue
• Rejection involves both humoral & CMI
TONY SCARIA 2010
KMC

21-04-2018
TONY SCARIA 2010
KMC
Hyperacute rejection
• d/t preformed Ab against graft
• With in minutes to hours after
transplantation
• Type II hypersensitivity
• Ag Ab reaction  compliment
formation  arteriolar fibrinoid
necrosis neutrophilic infiltrate &
fibrin platelet microthrombi
TONY SCARIA 2010
KMC

21-04-2018
Acute rejection
• Days or months
• Acute cellular rejection
• Interstitial mononuclear infiltrate
• Acute humoral rejection
• Type II hypersensitivity
• Intimal thickening & necrotising vasculitis 
REJECTION vasculitis
• Complement C4d deposition in blood vessels
TONY SCARIA 2010
KMC
c/c rejection
• Over months to years
• Arteries will show obliterative
intimal fibrosis
TONY SCARIA 2010
KMC

21-04-2018
Graft vs host ds
• Runt disease
• Involves both CD4 & CD8 lymphocytes (class I & II MHC)
• It occurs when
• Donor is immunocompetent
• Recipient is immunosuppressed
• It occurs during
• Solid organ transplantation with rich in lymphoid cells
• Mc with allogenic bonemarrow transplantation
• All organs can be affected but rare with lungs
• Transfusion of unirradiated blood
TONY SCARIA 2010
KMC
TONY SCARIA 2010
KMC

21-04-2018
Sex linked graft rejection
Graft rejection if
male sibling is
donor for female
TONY SCARIA 2010
KMC
Sex linked graft rejection
• Eichwald slimser effect
• Y linked graft rejection
• Ubiquitously transcribed tetraicopeptide repeat containg y linked
graft rejection (UTY )
• UTY gene codes for histone demethylase UTY (contain HY transplant Ag)
• Minor histoincompatibility gene
TONY SCARIA 2010
KMC

21-04-2018
Diseases of immune system
TONY SCARIA 2010
KMC
Immunodeficiency
TONY SCARIA 2010
KMC

21-04-2018
Brutons agammaglobulinemia
• d/t mutation in in cytoplasmic tyrosine kinase called b cell tyrosine
kinase (BtK)failure of maturation of pro B cells & pre B cells
• Humoral immunity is affected
• Depletion of B cell areas of LN(cortical follicle & medullary cord) & spleen
(mantle layer perifollicular region germinal centre)
TONY SCARIA 2010
KMC
• It is an X linked ds
• Manifested only in boys
TONY SCARIA 2010
KMC

21-04-2018
Brutons agammaglobulinemia
• Normal CMI defective humoral immunity
• Not usually manifested under 6 months when maternal Ig are deficient
• Normal until 6 months (until when maternal Ig are present )
• No serum Ig
• Plasma cells are absent in all tissues
TONY SCARIA 2010
KMC
Broutons gammaglobulinemia
• Boys are affected
• B cells are affected
• Bacterial infections
TONY SCARIA 2010
KMC

21-04-2018
X linked  boys are only affected
TONY SCARIA 2010
KMC
The nude mouse
TONY SCARIA 2010
KMC

21-04-2018
Digeorge syndrome
• Thymic hypoplasia
• T cell abnormality
• Defective immunity against fungi & viruses
TONY SCARIA 2010
KMC
TONY SCARIA 2010
KMC

21-04-2018
Mutation in TBX1 gene of 22q11.2
• TBX1 gene on chromosome 22
q 11.2
TONY SCARIA 2010
KMC
Embryology of thymus
TONY SCARIA 2010
KMC

21-04-2018
TONY SCARIA 2010
KMC
Tetrology of fallot
TONY SCARIA 2010
KMC

21-04-2018
Wiskott Aldrich syndrome
TONY SCARIA 2010
KMC
Clinical features
• X linked recessive
• Triad
• Thrombocytopenia
• Infections (recurrent)
• Eczema
TONY SCARIA 2010
KMC

21-04-2018
• Low IgM
• Elevated Ig A & E
• Normal Ig G
• Increased risk of Hodgkins lymphoma
TONY SCARIA 2010
KMC
TONY SCARIA 2010
KMC

21-04-2018
• The thymus is initially normal, but there is progressive age-related
depletion of T lymphocytes in the peripheral blood and lymph nodes,
with concurrent loss of cellular immunity.
• Additionally, patients do not effectively synthesize antibodies to
polysaccharide antigens, and are therefore particularly susceptible to
encapsulated, pyogenic bacteria
• only treatment is bone marrow transplantation
TONY SCARIA 2010
KMC
SCID
• Severe Combined Immunodeficiency
TONY SCARIA 2010
KMC

21-04-2018
TONY SCARIA 2010
KMC
SCID
• Lymphnode tonsils adenoids peyers patches are absent
TONY SCARIA 2010
KMC

21-04-2018
Other causes of SCID
• Jak3 mutation
TONY SCARIA 2010
KMC
TONY SCARIA 2010
KMC

21-04-2018
Bare lymphocyte syndrome
• Defective expression of MHC class I or class II
• 2 types
• Type I Lack expression of class I
• type II  lack expression of cass II
TONY SCARIA 2010
KMC
TONY SCARIA 2010
KMC

21-04-2018
Hyper IgM syndrome
TONY SCARIA 2010
KMC
hyperIgM syndrome
TONY SCARIA 2010
KMC

21-04-2018
Isolated IgA Deficiency
• Extremely low levels of IgA (secretory & serum )
• IgM and IgG subclasses of antibodies are present in normal or even
supranormal levels
• pathogenesis of IgA deficiency seems to involve a block in the
terminal differentiation of IgA-secreting B cells to plasma cells
• Asymptomatic
• weakened mucosal defenses predispose patients to recurrent
sinopulmonary infections and diarrhea
• Tranfusion with normal IgA  anaphylactic reactionTONY SCARIA 2010
KMC
Common variable immunodeficiency
• Hypogammaglobulinemia
generally affecting all classes
but sometimes only IgG
• Normal number of B Cells
defective maturation of B cells
to plasma cells
• Increased chance of diaarhea
by giardia lamblia
TONY SCARIA 2010
KMC

21-04-2018
Increased chance of Giardia lamblia infns
• Selective IgA deficiency
• X linked agammaglobulinemia
• Common variable immunodeficiency
TONY SCARIA 2010
KMC
Defective phagocytosis
• Chediak higashi syndrome
• Chronic granulomatous disorder
• Jobs syndrome
TONY SCARIA 2010
KMC

21-04-2018
Chediak higashi syndrome
• Autosomal recessive disorder
• Lysosomal protein trafficking disorder
• Lysosomes cannot fuse with
phagosome to form phagolysosome
• Impaired phagolysosome function
• Neutrophils
• Neutropneia
• Giant primary granules
• Defective chemotaxis for neutrophils
• Defective melanocytes  albinism
• Defective schwann cells  neurological
symptoms TONY SCARIA 2010
KMC
TONY SCARIA 2010
KMC

21-04-2018
Chronic granulomatous disease
• X linked
• Defective NADPH oxidase
• Defective production of H2O2
major reason for defective
bactericidal activity
• Increased chance of infection by
catalse positive bacteria
(staphylococci / coliform)
• But catalse negative (streptococci
& pneumococci) are handled
normally TONY SCARIA 2010
KMC
Nitrblue tetrazolium test for CGD
CGD patients are/were diagnosed with a Nitroblue Tetrazolium test which is
abnormal/negative (fails to turn a blue color like it should). This test is/was
used primarily to differentiate CGD from the similar MPO deficiency.
TONY SCARIA 2010
KMC

21-04-2018
Nitroblue tertrazolium test
• Negative in CGD d/t deficiency of NADPH oxidase
NADPH oxidase
TONY SCARIA 2010
KMC
TONY SCARIA 2010
KMC

21-04-2018
Jobs syndrome
• Hyper IgE syndrome
• AD disorder
• Defect in phagocytosis
TONY SCARIA 2010
KMC
Amyloidosis
TONY SCARIA 2010
KMC

21-04-2018
• Amyloid is misfolded protein that takes the form of a beta-pleated
sheet
• the protein cannot be degraded by cellular enzymes
• results in accumulation in the extracellular space
• the deposited mass of the misfolded protein is damaging to tissues
TONY SCARIA 2010
KMC
• Amyloidosis
• May be generalised
• May be localised
TONY SCARIA 2010
KMC

21-04-2018
• Diagnosis made by
demonstrating
• apple-green birefringence
of Congo red stain under
polarized light
TONY SCARIA 2010
KMC
Localised
TONY SCARIA 2010
KMC

21-04-2018
TONY SCARIA 2010
KMC
To detect cross β pleated sheat
• X ray crystallography
• IR spectroscopy
TONY SCARIA 2010
KMC

21-04-2018
B pleated structure is responsible for congo
red apearance
TONY SCARIA 2010
KMC
TONY SCARIA 2010
KMC

21-04-2018
Cross section of amyloid myocardium stained
with Lugol's iodine solution.
TONY SCARIA 2010
KMC
Amyloid material consist of
• 95 % fibril protein
• 5% P component
TONY SCARIA 2010
KMC

21-04-2018
TONY SCARIA 2010
KMC
Primary amyloidosis
• Most common type
• Seen with plasma cell disorders
• AL type amyloidosis (λ chain of
Ig)
• Organs involved
• Heart
• GIT
• Respiratory tract
• Skin
• Peripheral N
• Tongue
TONY SCARIA 2010
KMC

21-04-2018
TONY SCARIA 2010
KMC
• In primary amyloidosis mc cause of death is CHF
• AL amyloid can bind and inhibit factor X  bleeding diathesis
TONY SCARIA 2010
KMC

21-04-2018
Secondary amyloidosis
• It is seen in
• c/c inflammatory
conditions
• RA  MC cause
• Non immunocyte
tumours like hodgkins
lymphoma & RCC
TONY SCARIA 2010
KMC
RA most common cause of secondary
amyloidosis
TONY SCARIA 2010
KMC

21-04-2018
Β2 macroglobulin in hemodialysis associated
amyloidosis is deposited in joint synovium tendon
sheath BUT NOT IN BONES
TONY SCARIA 2010
KMC
Amyloidosis of individual organs
• Kidney
• Mc & serious involvement
• MC presentation is massive proteinuria
• Primarily seen in glomeruli but it may involve interstitial peritubular tissue
arteries & arterioles
• But NOT AROUND VENULES OF KIDNEY
TONY SCARIA 2010
KMC

21-04-2018
Initially deposited in mesangial
matrix
TONY SCARIA 2010
KMC
TONY SCARIA 2010
KMC

21-04-2018
Amyloid deposits mainly occur in glomeruli
TONY SCARIA 2010
KMC
TONY SCARIA 2010
KMC

21-04-2018
Amyloidosis in kidney
TONY SCARIA 2010
KMC
Sago spleen  deposited in follicles of spleen
 tapioca like granules
TONY SCARIA 2010
KMC

21-04-2018
Lardaceous spleen  deposited in red pulp
diffuse geographical areas of amyloid
TONY SCARIA 2010
KMC
TONY SCARIA 2010
KMC

21-04-2018
Amyloidosis of heart
• Amyloid deposits in
subendocardial space of atria
initially
TONY SCARIA 2010
KMC

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