SUBMITTED BY:Jasleen RajpalDeeksha SinghRia Sara ThomasPriyanka MathurParul Yadav{btech biotech6th semester}

Topics:1. Major histocompatibility complex

2. superantigens

SUBMITTED TO:Ms. Ravneet ChugFaculty immunology

INTRODUCTION

MAJOR

HISTOCOMPATIBLITY

COMPLEX

1.MHC{Major Histocompatility Complex}

Every mammalian species studied till date

possesses a tightly linked cluster of genes, the

major histocompatibility complex, whose products

play roles in intercellular recognition and in

discrimination between self and non self.

The MHC participates in the development of

both humoral and cell mediated immune

responses.

most T cells recognize antigen only when it is

combined with an MHC molecule.

For this reason, the MHC partly determines the

response of an individual to antigens of infectious

organisms, and it has therefore been implicated

in the susceptibility to disease and in the

development of autoimmunity.

The recent understanding that natural killer cells

express receptors for MHC class I antigens and

the fact that the receptor–MHC interaction may

lead to inhibition or activation expands the known

role of this gene family .

The major histocompatibility complex is a

collection of genes arrayed within a long

continuous stretch of DNA on chromosome 6 in

humans and on chromosome 17 in mice. The

MHC genes are organized into regions encoding

three classes of molecules :

Class I MHC genes encode glycoproteins

expressed on the surface of nearly all nucleated

cells; the major function of the class I gene

products is presentation of peptide antigens to TC

cells.

Class II MHC genes encode glycoproteins

expressed primarily on antigen-presenting cells

(macrophages, dendritic cells,and B cells),where

they present processed antigenic peptides to TH

The class I and class II MHC molecules have

common structural features and both have roles

in antigen processing.

By contrast, the class III MHC region, which is

flanked by the class I and II regions, encodes

molecules that are critical to immune function but

have little in common with class I or II molecules.

Class III products include the complement

components C4, C2, BF, and inflammatory

cytokines, including tumor necrosis factor (TNF)

and heat-shock proteins.

MHC are highly polymorphic; that is, many

alternative forms of the gene, or alleles, exist at

each locus among the population

POINTS TO PONDER

Human MHC class I and II are also

called human leukocyte antigen (HLA).

To clarify the usage, some of the biomedical

literature uses HLA to refer specifically to the

HLA protein molecules and reserves MHC for

the region of the genome that encodes for this

molecule, but this is not a consistent

convention.

The most studied HLA genes are the nine

classical MHC genes: hla-a, hla-b, hla-c, hla-

dpa1, hla-dpb1, hla-dqa1, hla-dqb1, hla-dra,

and hla-drb1. In humans, the MHC gene

cluster is divided into three regions: classes I,

The class I and class II gene products shown in

this figure are considered to be the classical MHC

molecules. The class III gene products include

complement (C) proteins and the tumor necrosis

factors (TNF- and TNF-).

NATURE OF MHC

1. Polygenic – 9 main gene

2. Polymorphic- multiple alleles for each

genes

3. Co dominant – both maternal and paternal

alleles are expressed equally

Class I MHC molecules STRUCTURE

Contain a 45-kilodalton (kDa) alpha chain

associated non covalently with a 12-kDa beta

2-microglobulin molecule.

The alpha chain is a transmembrane

glycoprotein encoded by polymorphic genes

within the A, B, and C regions of the human

HLA complex and within the K and D/L regions

of the mouse H-2 complex .

Beta 2-Microglobulin is a protein encoded by a

highly conserved gene located on a different

chromosome.

Association of the alpha chain with beta 2-

The alpha chain is anchored in the plasma

membrane by its hydrophobic

transmembrane segment and hydrophilic

cytoplasmic tail.

Structural analyses have revealed that the α

chain of class I MHC molecules is organized

into three external domains (α1, α2, and α3),

Each containing approximately 90 amino acids;

a transmembrane domain of about 25

hydrophobic amino acids followed by a short

stretch of charged (hydrophilic) amino acids; and

a cytoplasmic anchor segment of 30 amino acids.

The β2-microglobulin is similar in size and

organization to the α3 domain; it does not contain

a transmembrane region and is noncovalently

bound to the class I glycoprotein.

The α3 domain and β2-microglobulin are

organized into two β pleated sheets each formed

by antiparallel β strands of amino acids

FUNCTION

Class I MHC molecules bind peptides and

present them to CD8+ T cells.

These peptides are derived from

endogenous intracellular proteins that are

digested in the cytosol and then transported to

cisternae of the ER, where they interact with

class I MHC molecules.

This process, known as the cytosolic or

endogenous processing pathway

Class II MHC moleculesSTRUCTURE

Contain two different polypeptide chains, a 33-kDa

α chain and a 28-kDa β chain, which associate by

non covalent interactions.

Like class I α chains, class II MHC molecules are

membrane-bound glycoproteins that contain

external domains, a transmembrane segment, and

a cytoplasmic anchor segment.

Each chain in a class II molecule contains two

external domains: α1 and α2 domains in one chain

and β1 and β2 domains in the other.

The membrane-proximal α2 and β2 domains, like

the membrane-proximal α3/β2-microglobulin

domains of class I MHC molecules, bear sequence

similarity to the immunoglobulin-fold structure; for

The membrane-distal portion of a class II molecule

is composed of the α1 and β1 domains and forms

the antigen binding cleft for processed antigen.

The class II molecule lacks the conserved residues

that bind to the terminal residues of short peptides

and forms instead an open pocket.

REACTION TO BACTERIA

Because class II MHC is loaded with

extracellular proteins, it is mainly concerned

with presentation of extracellular pathogens

(eg, bacteria that might be infecting a wound).

Class II molecules interact mainly with

immune cells, like the T helper cell (TCD4+) .

Which then help to trigger an appropriate

immune response which may include

localized inflammation and swelling due to

recruitment of phagocytes or may lead to a full-

force antibody immune response due to

activation of B cells.

Besides antigen presentation, growing

evidence is showing that ligation of MHC class

SUPER ANTIGENSuperantigens are class of antigen that causes non-

specific activation of T-cells which further causes

polyclonal activation of T-cell and cytokine release.

Superantigens are produced by some pathogenic

viruses and bacteria as a defense mechanism against

immune system. Compared to normal antigen induced

T-cell response where 0.0001-0.001% of the body’s

cell are activated these superantigens are capable of

activating up to 25% of body’s T-cell

Large number of activated T-cell produce a massive

immune response which is not specific to any

particular epitope on the S.Ag thus it undermines one

of the fundamental strength of the adaptive immune

system that is its ability to target antigen with high

specificity.

Large number of activated T-cell release large

amount of cytokines, most important of which is IFN

gamma. The excess amount of interferon gamma in

turn activate macrophages.

The activated macrophages in turn overproduce

proinflammatory cytokines such as IL-1,IL-6 and TNF

–alpha.

TNF-alpha is particularly important as body’s

inflammatory response. In normal circumstances it is

released in low level and help the immune system to

defeat the pathogen but when it is released in high

level (due to mass T-cell activation from Sag) can

cause severe and life threatening symptoms such as

Shock and Multiple organ faliure.

StructureSuperantigens are produced by the bacteria

intracellularly and are release upon infection as

mature extracellular toxin,

The sequence of these toxins are similar among

different subgroup .

The 3D structure is also similar among different SAg

which result in similar functional effect among different

group.

The structure of Sags is compact and ellipsoidal and

comprise 2 domain folding pattern.

One domain has binding region for MHC-II and 2nd

domain has binding region for Tcell.

BindingThe Superantigen first bound to MHC-II and then are

coordinated to the variable beta chain of T-cell

BINDING WITH MHC-II

SAg show preference for HLADQ form of cell surface

receptor found on APC. It is alpha-beta hetrodimer of

class II MHC. Several staphylococcus SAg are capable

of crosslinking by binding with both alpha and beta

chain.

This mechanism stimulate cytokine expression and

release in APC as well as inducing the production of co-

stimulatory molecule that allow the cell to bind and

activate the T-cells.

BINDING WITH T-CELL

T-cell binding region of Superantigen bind with the

variable region on beta chain of T-cell receptor.

A particular SAg can activate large proportion of T-cell

population because humans contain only 50types of

variable region on beta chain and some superantigens

are capable of binding with multiple type of variable

TreatmentPrimary goal of treatment is to remove the microbe

that is producing the antigen. This is done by the

vasopressors, fluid resuscitation and antibiotics.

Our body naturally produces antibodies against some

SAg, this effect is augmented by stimulating B cell

production of these antibodies.

Synthetic antibodies and peptides are produced that

mimic the SAg binding region on MHC II, this blocks

the interaction of Sag with MHCII and prevent T cell

activation.