11/26/2014

1

Lymphocytes

Lymphoid Organs

MHC

Structure & Function of the Immune System

Dr Debasis Biswas

We already know Lymphocytes: 20- 40% of WBC populn.

T, B, NK

NK: no surface marker for ag recognition

T, B: Nave Lymphoblasts ..

Effector & Memory

Nave: 6 Lymphoblast: 15 Plasma Cell: 15

ing Cytoplasm: Nucleus ratio

ing Organellar Complexity (ER; Golgi)

Maturation: Bursa of Fabricius (birds)

Bone marrow (mammals)

Specific marker for ag recogn: sIg molecule

Soluble ag

Activation.. Blast Transformation & Clonal

Proliferation Effector cells (= Plasma

cells; secrete antibodies) & Memory cells

B cells

Maturation: Thymus

Specific marker for ag recogn: T cell receptor

MHC-bound ag on APCs or on virus- infected

cells or cancer cells or grafts

Pan T cell marker: CD3

Helper T cell: CD4; Cytotoxic T cell: CD8

Normally TH: CTL= 2:1

T cells

TH cellsActivation (MHC Class II)

Blast Transformation & Clonal Proliferation...

Effector cells

(= Activated Th cells; secrete cytokines that activate CTLs, APCs, M, B cells) &

Memory cells

Effector TH cells

Cytokine profileTH1: Supports

Inflammation; CMI

TH2: Supports

Humoral immunity

CTLsActivation (MHC Class I)

Blast Transformation & Clonal Proliferation...

Effector cells

(= Activated CTLs; eliminate altered self cells & grafts) &

Memory cells

T cells

T cell Receptor, linked

to CD3

CD2 ag.. Bind to

Sheep RBCs

Mitogens: PHA, ConA

No surface projections

B cells

sIg

Bind to Sheep RBCs coated

with Ab & Complement

(CR2 for C3)

Mitogens: LPS, EB virus

Filamentous surface with

microvilli

T cells vs B cells

11/26/2014

2

Primary Lymphoid Organs

Maturn. of lymphocytes

to achieve ag specificity

Thymus (T cells)

Bone Marrow (B cells)

Secondary Lymphoid Organs

Interaction of lymphocytes

with antigen

Lymph Nodes

Spleen

Mucosa- Associated

Lymphoid Tissue (MALT)

Lymphoid Organs 1ry Lymphoid Organs:Thymus

Bone Marrow

2ry Lymphoid Organs:

Lymph Node

Spleen

MALT

Cutaneous Associated

Lymphoid Tissue

Thymus

Cortex: Packed with immature T cells (Thymocytes)

Medulla: Sparsely populated with Thymocytes

Lymph node

Cortex

Paracortex

Medulla

Capsule

Primary

Lymphoid

Follicles

Germinal

Centers

Cellular network

to trap antigens

in lymphatic fluid

B cells, M, Follicular DCs: 1ry follicle

2ry follicle with GC

Ag stimulnT cells, Intdg DCs

Primary

Lymphoid

Follicles

Germinal

Centers

Afferent

Lymphatics

Paracortex:

Ag presentn by IDCsStimulation of TH cells

Initial activn of B cells

Foci of proliferating B cells

Diffn. into plasma cells

Cortex:

Migration of B cells &

TH cells to 1ry follicles

Cortex:

2ry follicles with GCsMedulla:

Migration of

Plasma cells

from

2ry follicles

Paracortex Spleen White Pulp: PALS (T cells) + 1ry lymphoid follicles (B cells)

+ Marginal Zone (Lymphocytes + Mes)

Red Pulp: RBCs; Mes

11/26/2014

3

Splenic

Artery

Marginal Zone:

Ag presentn by IDCs

Migration of activated

B & TH cells to 1ry follicles

PALS:

Migration of IDCs

Stimulation of TH cells

Initial activn of B cells

2ry follicles with GCs Mucosal Associated Lymphoid

Tissue (MALT)

Mucous memb. of GIT, GUT, Resp. Tract: Major rt.

of ag entry

MALT: Defend these memb surfaces

Tonsils: Lingual; Palatine; Pharyngeal Peyers Patches: Int. submucosa

Epithelial layer:

Intra-ep. Lymphocytes (IEL)

mostly T cells

M cells (on inductive site)

Lamina propria:

Loose clusters of B cells,

Plasma Cells, TH cells, M

Submucosa:

Peyers patches with

Lymphoid Follicles

MALT in Int mucosa

M cell: Ag entry by endocytosis

Basolatl pocket: B cells, TH cells, M

Ag delivery to Lymphocytes Activn: B cells in lym. follicles

Plasma cells: IgA ab

Major Histocompatibility ComplexHuman: HLA

Chromosome 6

Mouse: H-2

Chromosome 17

Structure of MHC molecules

Membrane- bound glycoproteins

11/26/2014

4

Structure of MHC molecules

Class I: 45 kDa chain

+ 12 kDa 2 microglobulin

chain: 1; 2; 3 domains

Between 1 2 domains: Peptide- binding groove

Class II: 33 kDa chain

+ 28 kDa chain

chain: 1; 2 domains

chain: 1; 2 domains

Between 1 2 domains:

Peptide- binding groove

MHC genes, mRNA transcripts &

protein molecules

Major Histocompatibility Complex

Class I: All nucleated cells Ag presentn to TC cells

Class II: APCs (DCs, M, B) Ag presentn to TH cells

Class III: Secreted . Assoc. with immune fx & inflammn.

Inheritance of MHC genesHighly Polymorphic: Many alt. forms of genes (alleles) at each locus

Gene loci lie close together: Low recombination frequency

Genes inherited as 2 sets.. 1 from each parent. Each set: Haplotype

Co-dominant expression: Both parental haplotypes expressed in the

same cells

1 in 4 chance siblings have same HLA haplotypes .. Histo-compatible

Recombination within MHC genes

Though infrequent,

Recombination leads to

diversity of alleles

within populations.

Peptide in the groove

11/26/2014

5

Peptide binding groove

Class I: Groove closed at both ends

Ends of peptide anchored

Peptide: Endogenous; 8- 10 a.a.

Specific a.a. at N & C terminii

Ends fixed with the middle arched

up away from the MHC molecule

Class II: Open ended groove

Peptide: Exogenous;

13- 18 aa;

Binding sites distributed

throughout the groove,

rather than at the ends

Association of some HLA alleles observed with

certain diseases

Quantified as Relative Risk: Frequency of the allele

in the disease populn, compared to general populn

Ankylosing Spondylitis... HLA B27 90

Hereditary Hemochromatosis ..A3/ B14 ... 90

Narcolepsy . DR2 130

Insulin Depdt DM DR4/ DR3 .. 20

Goodpastures Syndrome DR2 16

MHC & Disease Susceptibility

Hypothesis:

Specific alleles may account for differences in the immune responsiveness to particular antigens arising from variation in the ability to present processed antigen or the ability of T cells to recognize presented antigen.

Specific alleles may also encode molecules that are recognized as receptors by viruses or bacterial toxins

MHC & Disease Susceptibility