Introduction

• HLA= Human Leukocyte Antigen
• Located on Chromosome 6
• 3 groups of proteins (I,II,III)
• Class I

A,B,or C

• Class II

DP,DQ,DR

• Class III

complement components (C4, B1, C2)

MHC Class I Molecules

• Location- A,B,C
• associated w/ b₂-microglobulin on cell surface
• co-dominant (half from mommy and ½ from daddy)
• with b₂-microglobulin forms 4 domains
• binds oligopeptides
• the a.a. differences are responsible for Ag and TcR binding
• FOUND ON ALL NUCLEATED CELL MEMBRANES

MHC CLASS II Molecules

• Location- D
• gene expression similar to MHC-I
• 2 chains- ab each has 2 domains
• Constituitive expression- in other words, found mainly on B cells, dendritic cells, and the thymic epithelium
• Inducible expression- in other words, if induced they can show up on macrophages and activated T cells

MHC Class III Molecules

• We don’t have to know much
• they constitute some of the complement components

Role of MHC in controlling T Cell responses

• During processing they become associated with Ag and the MHC-peptide complex binds to the TcR on T Helper cells. The CD3 associated with the TcR activates the T cell.

MHC Restriction + Who Kills Who and Why?

• CD4- Class II restricted
• CD8- Class I restricted
• Immune T Cells are “not only restricted by virus, but MHC background also”
• Remember, different people have different HLA specificity, this accounts for the number of organ transplant rejections that occur.
• If you grow someone else’s HLA derived MHC Class molecule on a B cell that doesn’t match yours, and then infect this B cell with a virus and then inject it in yourself you will have NO T cell response to that antigen-B cell complex because the HLA in that other person has encoded for a different MHC Class molecule on their B cell that your TcR on your T cell doesn’t recognize. Likewise there will be no T cell response to an injection of the other person’s HLA derived MHC Class molecule on a B cell because your TcR can’t recognize it.
• Consequently, If you take your very own or your identical twin’s (should be exact) HLA derived MHC Class molecule on a B Cell and incubate it with a virus, and then inject this B cell-antigen mixture into yourself you definitely WILL HAVE a T cell response to this antigen-B cell complex. This occurs because your TcR receptors can readily identify the MHC Class molecule on the B cell that is holding on to the antigen which then allows for CD3 to activate the T cell and subsequently kill the antigen.
• However, if you don’t add any virus to your own or your identical twin’s HLA derived MHC Class molecule on a B cell and inject it into yourself, you will have NO T cell response to this injection because the TcR receptor will not identify the B cell’s MHC Class molecule as foreign unless it is bound to an antigen.
• To answer the question as to why you don’t kill the “foreign” concoction? You do end up taking care of it, but it takes a longer period of time to identify the entire complex as foreign. There is no immediate killing because of the TcR’s lack of recognition to the other type of MHC Class I molecule. Later on, the entire complex will be identified as foreign and then eliminated.

Activity of CD8+ CTL

• remember it is the IFN-g from the T_H1 cell that helps activate the T_C cell in cellular immunity
• 1^st signal- antigen-MHC complex
• 2^nd signal- IFN-g, _{SOME IL-2}
• Lysis of the targeted infected cell

1. attachment- TcR specific for that antigen; adhesion molecules
2. Intracellular granules in T_C cell

a.     mobilizes towards target

b.     RELEASES CONTENTS (Perforins)

c.      Complement-like effect (drills holes in the membrane causing leakage)

1. Lymphotoxin- (TNF-b)- Tumor necrosis factor-b- can cause cell lysis or apoptosis directly.
2. Target Cell Release

Factors that Determine MHC Restriction for Antigens

Class II Restriction

1.     EXOgenous antigens

2.     requires phagocytosis into APC

3.     MHC-peptide complex sent to APC surface for presentation to CD4

Class I Restriction

1.     ENDOgenous antigen

2.     Antigen must enter the cell on its own

3.     in cytosol or ER, Class I-peptide association occurs

4.     Expressed on Cell surface of target for presentation to CD8+

Route of Infection Determines MHC Restriction (Can be both CD4 and CD8 mediated)

Relationship of MHC Expression to Human Disease

• most diseases are immunologic
• autoimmune or post viral
• Etiologic agents unknown (Etiologic = cause or origin)
• Theoried Mechanisms

1. MHC as a receptor for pathogens
2. suppression of response to pathogen (molecular mimicry)
3. “hole in the repertoire”-incapable of recognition- “not one vaccine is 100% effective in a population because of this”
4. MHC-linked locus is moved, deleted, or damaged
5. NOBODY REALLY KNOWS

• KNOW that there are many associations of diseases with certain HLA types
• HLA B27 is a watch-out sign
• This can cause many types of autoimmune diseases
• The relative risk factor with this HLA B27 allele is high for getting the disease
• HLA B8 is involved in Myasthenia gravis and Graves disease.

Tags: cytosol, Grave's disease, HLA, HLA B27, HLA B8, immunologic, Major Histocompatability Complex, MHC, molecular mimicry, myasthenia gravis, pathogens, receptor

This entry was posted on Thursday, March 12th, 2009 at 5:14 am and is filed under Immunology. You can follow any responses to this entry through the RSS 2.0 feed. Responses are currently closed, but you can trackback from your own site.