1 immunology-csbrp

Disorders of Disorders of ImmunityImmunity

Dr.CSBR.Prasad, Dr.CSBR.Prasad, M.D.M.D.

Immune SystemImmune System AntigenAntigen

Protein substance that stimulates Protein substance that stimulates Antibody productionAntibody production

HaptenHapten – non-protein substance, – non-protein substance, Small mol.wt.Small mol.wt.

AntibodyAntibody Protein substance produced as a Protein substance produced as a

result of antigen stimulationresult of antigen stimulation Circulating Ab are immunoglobulinsCirculating Ab are immunoglobulins

Can you name Can you name one carbohydrate one carbohydrate

antigen?antigen?Blood group Blood group

antigens (ABO sys)antigens (ABO sys)

Immune SystemImmune System Non- Specific Immunity (Innate Non- Specific Immunity (Innate

immunity)immunity)--first line of defence without antigenic first line of defence without antigenic specificityspecificity Humoral – Complement systemHumoral – Complement system Cellular – Neutrophils, MØ, NK cellsCellular – Neutrophils, MØ, NK cells

Specific Immunity (Adaptive immunity)Specific Immunity (Adaptive immunity) Humoral .I - Antibody produced by B cellsHumoral .I - Antibody produced by B cells Cell mediated .I – T cells - produce Cell mediated .I – T cells - produce

Sensitized cellsSensitized cells

Immune SystemImmune System LymphocytesLymphocytes

T lymphocytesT lymphocytes B lymphocytesB lymphocytes

MacrophagesMacrophages Natural killer cells (NK cell)Natural killer cells (NK cell) Dendritic cellsDendritic cells CytokinesCytokines Complement systemComplement system

Immune SystemImmune SystemLymphocytesLymphocytes T lymphocytesT lymphocytes

60-70% peripheral lymphocytes60-70% peripheral lymphocytes Paracortical areas of lymph nodeParacortical areas of lymph node Perifollicular sheaths of spleenPerifollicular sheaths of spleen

T cell Receptor (TCR) – T cell Receptor (TCR) – recognizes specific cell bound recognizes specific cell bound antigenantigen

T cell Receptor (TCR)T cell Receptor (TCR) 95% of TCR is a disulfide linked 95% of TCR is a disulfide linked

heterodimer consisting of alpha heterodimer consisting of alpha and beta polypeptide chainand beta polypeptide chain

Gamma and delta polypeptide Gamma and delta polypeptide chains seen at epithelial surfaces chains seen at epithelial surfaces eg. Respiratory / GIT mucosaeg. Respiratory / GIT mucosa

CD3 proteins are involved in CD3 proteins are involved in transduction of signals into the T transduction of signals into the T cells after it has bound to antigencells after it has bound to antigen

The T-cell receptor (TCR) complex. A, Schematic illustration of TCRα and TCRβ chains linked to

the CD3 complex.

The T-cell receptor (TCR) complex.The T-cell receptor (TCR) complex:B, Recognition of MHC-associated peptide displayed on an antigen-presenting cell (top) by the TCR. Note that the TCR-associated ζ chains and CD3 complex deliver signals (signal 1) upon antigen recognition, and CD28 delivers signals (signal 2) upon recognition of costimulators (B7 molecules).

T - lymphocytesT - lymphocytes Expresses non polymorphous Expresses non polymorphous

function associated molecules – function associated molecules – CD4, CD8 and accessory molecules CD4, CD8 and accessory molecules – CD2,CD9, CD28 and CD40 ligand– CD2,CD9, CD28 and CD40 ligand

CD4 is expressed on 60% of T cells CD4 is expressed on 60% of T cells (Helper T cell)(Helper T cell)

CD8 is expressed on 30% of T cells CD8 is expressed on 30% of T cells (cytotoxic T cell)(cytotoxic T cell)

Markers for B & T cellsMarkers for B & T cells T cell markers are unidigits (Eg: T cell markers are unidigits (Eg:

CD3)CD3) B cell markers are double digits B cell markers are double digits

(Eg: CD20)(Eg: CD20)

T - lymphocytesT - lymphocytes CD4 binds to Class II MHC CD4 binds to Class II MHC

molecule expressed on APCmolecule expressed on APC CD8 binds to Class I MHC CD8 binds to Class I MHC

moleculemolecule CD4+ T cell CD4+ T cell - Master regulator - Master regulator

Influences the function of other T Influences the function of other T cells, B cells, macrophages & NK cells, B cells, macrophages & NK cellscells

T - lymphocytesT - lymphocytes T Helper- 1 (TH1) subsetT Helper- 1 (TH1) subset

Secretes IL-2 and gamma IFNSecretes IL-2 and gamma IFN Involved in delayed hypersensitivityInvolved in delayed hypersensitivity Macrophage activation and synthesis of Macrophage activation and synthesis of

IgG antibodyIgG antibody T Helper- 2 (TH2) subsetT Helper- 2 (TH2) subset

Secretes IL4 and IL5Secretes IL4 and IL5 Involved in the synthesis of IgE antibodyInvolved in the synthesis of IgE antibody

CD8 T lymphocytes CD8 T lymphocytes secretes IL-2 and gamma IFNsecretes IL-2 and gamma IFN Act as cytotoxic cellsAct as cytotoxic cells

B - lymphocytesB - lymphocytes 10-20 % of circulating lymphocytes10-20 % of circulating lymphocytes Present in BM, germinal centre of Present in BM, germinal centre of

lymphnode and white pulp of spleenlymphnode and white pulp of spleen Activation of B- lymphocytes – Activation of B- lymphocytes –

plasma cells – secretes Ig (humoral plasma cells – secretes Ig (humoral Immunity)Immunity)

IgM present on all B cells form the IgM present on all B cells form the antigen binding component of B antigen binding component of B cell receptorcell receptor

MacrophagesMacrophages Part of Mononuclear phagocytic Part of Mononuclear phagocytic

systemsystem Process and present antigen to Process and present antigen to

immunocompetent T cellsimmunocompetent T cells Important for delayed hypersensitivity Important for delayed hypersensitivity

reaction. Gamma IFN secreted by T reaction. Gamma IFN secreted by T Helper-1 (TH1) subset enhances Helper-1 (TH1) subset enhances microcidal properties of macrophagemicrocidal properties of macrophage

Phagocyte the microbes that are Phagocyte the microbes that are opsonized by IgG or C3bopsonized by IgG or C3b

Dendritic CellsDendritic Cells Interdigitating dendritic cellsInterdigitating dendritic cells

Present in lymphoid cells, interstitium of Present in lymphoid cells, interstitium of heart and lungheart and lung

Epidermis – Langerhans cellEpidermis – Langerhans cell Expresses MHC class II molecule and act as Expresses MHC class II molecule and act as

APC for T cells APC for T cells Follicular dendritic cellsFollicular dendritic cells

Germinal centre of lymphoid follicle in Germinal centre of lymphoid follicle in spleen and lymphnodespleen and lymphnode

Bear Fc receptor for IgG and hence can Bear Fc receptor for IgG and hence can trap antigen bound to antibodytrap antigen bound to antibody

The morphology and functions of dendritic cells (DC). A, The morphology of cultured dendritic cells.

B, The location of dendritic cells (Langerhans cells) in the epidermis.

C, The role of dendritic cells in capturing microbial antigens from epithelia and transporting them to regional lymph nodes.

Natural Killer (NK) cellNatural Killer (NK) cell 10-15% of peripheral blood lymphocyte10-15% of peripheral blood lymphocyte Larger than small lymphocyte and Larger than small lymphocyte and

contain azurophilic granulescontain azurophilic granules Large granular lymphocyteLarge granular lymphocyte First line of defence against tumour First line of defence against tumour

cells, viral infected cellscells, viral infected cells CD16 and CD56 positiveCD16 and CD56 positive Secretes gamma InterferonSecretes gamma Interferon Antibody Dependent Cell mediated Antibody Dependent Cell mediated

Cytotoxicity (ADCC)Cytotoxicity (ADCC)

CytokinesCytokines Messenger molecule of immune Messenger molecule of immune

systemsystem Short acting soluble mediators, Short acting soluble mediators,

involved in the induction and involved in the induction and regulation of immune responseregulation of immune response

CytokinesCytokinesFive groupsFive groups1. 1. Mediate Mediate naturalnatural immunity immunity

IL-1, IL-6, TNF- alpha IL-1, IL-6, TNF- alpha 2. 2. Regulate Regulate lymphocytelymphocyte growth, activation and growth, activation and

differentiationdifferentiation IL-2 & IL-4 – favours lymphocyte growth and Diff.IL-2 & IL-4 – favours lymphocyte growth and Diff. IL-10 & TGF-beta – downregulate immune responseIL-10 & TGF-beta – downregulate immune response

3. 3. Activation of Activation of inflammatory cellsinflammatory cells Gamma interferon, TNF alpha, lymphotoxin (TNF- beta), Gamma interferon, TNF alpha, lymphotoxin (TNF- beta),

MIFMIF4. 4. ChemokinesChemokines – – leukocyte movementleukocyte movement5. 5. Stimulation of Stimulation of hematopoiesishematopoiesis

GM-CSF & G-CSF act on committed progenitor cellsGM-CSF & G-CSF act on committed progenitor cells

CytokinesCytokines Produced by different cell typesProduced by different cell types

IL-1, TNF - alphaIL-1, TNF - alpha Act on many cell typesAct on many cell types

IL-2 act on T cell, B cell and NK cellIL-2 act on T cell, B cell and NK cell Act in 3 waysAct in 3 ways

Autocrine effect – IL-2Autocrine effect – IL-2 Paracrine effect - IL- 7 BM stromal Paracrine effect - IL- 7 BM stromal

cellscells Endocrine effect - IL-1, TNF – alpha Endocrine effect - IL-1, TNF – alpha

(acute phase reactant)(acute phase reactant)

CytokinesCytokines Cytokines mediate their effect by Cytokines mediate their effect by

binding to specific high affinity binding to specific high affinity receptorsreceptors

Useful in therapyUseful in therapy Control the harmful effect of Control the harmful effect of

inflammation/ tissue damaging inflammation/ tissue damaging immune responseimmune response

Enhances immunity against Enhances immunity against cancer/microbial infectionscancer/microbial infections

Histo-Histo-compatibility compatibility

Antigens - Antigens - HLAHLAChromosome # 6Identity of SELF

Histo-compatibility Histo-compatibility AntigenAntigen

Antigens that evoke rejection of Antigens that evoke rejection of transplanted organstransplanted organs

Principal function is to bind peptide Principal function is to bind peptide fragments of foreign protein for fragments of foreign protein for presentation to appropriate antigen presentation to appropriate antigen specific T cellsspecific T cells

MHC antigens – Human Leukocytic MHC antigens – Human Leukocytic Antigen (HLA)Antigen (HLA)

MHC antigens and corresponding MHC antigens and corresponding genes are complex in structuregenes are complex in structure

Histo-compatibility Histo-compatibility AntigenAntigen

Base on structure, distribution and Base on structure, distribution and function of MHC gene productsfunction of MHC gene products

Class I MHC antigensClass I MHC antigens have loci as have loci as HLA- A, HLA – B and HLA – CHLA- A, HLA – B and HLA – C

Class II MHC antigensClass II MHC antigens have single have single locus HLA – D . It has 3 subregions – locus HLA – D . It has 3 subregions – HLA- DP, HLA-DQ and HLA- DRHLA- DP, HLA-DQ and HLA- DR

Class III genesClass III genes - complement - complement

Class I MHC antigensClass I MHC antigens Expressed on all nucleated cells & Expressed on all nucleated cells &

plateletplatelet It binds to peptides that are It binds to peptides that are

derived from proteins such as viral derived from proteins such as viral antigensantigens

Cells process the antigen and Cells process the antigen and transported to cell surface for transported to cell surface for presentation to CD8 cytotoxic T presentation to CD8 cytotoxic T lymphocyteslymphocytes

Figure 6-10 Antigen processing and recognition. The sequence of events in the processing of a cytoplasmic protein antigen and its display by class I MHC molecules are shown at the top. The recognition of this MHC-displayed peptide by a CD8+ T cell is shown at the bottom.

Class II MHC antigensClass II MHC antigens Present only on APC – Macrophages, Present only on APC – Macrophages,

Dendritic cells & B cellsDendritic cells & B cells It binds to exogenous antigens It binds to exogenous antigens

(microbes, soluble proteins) that are (microbes, soluble proteins) that are first internalised and processed in first internalised and processed in endosomes / lysosomesendosomes / lysosomes

Peptide - MHC complex is Peptide - MHC complex is transported to the cell surface, where transported to the cell surface, where it is recognized by CD4 helper T cellsit is recognized by CD4 helper T cells

HLA & Disease HLA & Disease associationassociation

InflammatoryInflammatory Myesthenia gravis – HLA B8Myesthenia gravis – HLA B8 Ankylosing spondylitis- HLA B27Ankylosing spondylitis- HLA B27 Polygonococcal arthritis – HLA B27Polygonococcal arthritis – HLA B27 Salmonella arthritis – HLA B27Salmonella arthritis – HLA B27 Rheumatoid arthritis – HLA DR4Rheumatoid arthritis – HLA DR4 Chronic active hepatitis – HLA DR3Chronic active hepatitis – HLA DR3 Grave’s disease – HLA DR3Grave’s disease – HLA DR3

Inherited errors of metabolismInherited errors of metabolism 21 hydroxylase deficiency – HLA BW47 21 hydroxylase deficiency – HLA BW47

AutoimmunityAutoimmunity Insulin dependent diabetis – HLA DR4 Insulin dependent diabetis – HLA DR4

&DR3&DR3

OverviewOverview HI --- Ab synthesisHI --- Ab synthesis CMI --- Sensitized cellsCMI --- Sensitized cells TH1 is associated with IgG elaborationTH1 is associated with IgG elaboration TH2 is associated with IgE elaborationTH2 is associated with IgE elaboration NK cells are non-specific in their actionNK cells are non-specific in their action HLA-B27, HLA-DR3 & 4 are more HLA-B27, HLA-DR3 & 4 are more

commonly associated with diseasescommonly associated with diseases CytokinesCytokines

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