Genetic Control Of Human Leukocyte Antigens Hlas

A. Functions of HLAs. HLAs control several elements, including:

1. Discrimination between self and nonself

2. Antigen presentation to T cells, but only of the same HLA type (self-MHC restriction)

3. Susceptibility to immunologic disorders and infectious agents

-----

V3

-----

Vn

J1

----

_

Li |—j ..».:;,,j—

2. B-cell DNA

5'____

V1

-

V2 \ji

M jjisj_j CK I

3. Primary RNA transcript

4. mRNA

5. K Chain polypeptide

V2 J4

^Transcription

Splicing

Translation

NH2[ VK CK HCOOH

C1

J2

C2

J3

C3

J4

O

J5

C5

J6

Transcription

3. Primary RNA transcript

Splicing

>

r

| V1 ■

0=:>

4. mRNA

NH2

Translation

r

]vx

C2-.p COOH

5. X Chain polypeptide

Figure 5-1. (A) Kappa (k) light (L)-chain synthesis. From the pool of multiple variable (V) region genes on chromosome 2 in the germ line DNA (I), one V region gene is joined to a joining (J) region gene, resulting in B-cell DNA (2). Following removal of introns by recombinases, the primary RNA is transcribed (3), resulting in mRNA (4) composed of one V region gene, one J gene, and the constant (Ck) region gene. Translation of the mRNA results in the k L-chain polypeptide (5). (Redrawn with permission from Benjamini E: Immunology: A Short Course, 3rd ed. New York, Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc., 1996, p 98.) (B) Lambda (X) L-chain synthesis. Rearrangement and synthesis of the X L-chain genes occurs in an identical manner on chromosome 22, except for the availability of up to six CX- exons for union to the VJ combined exon. This availability results in several subtypes.

V1-V100 D1- D50 J1-J6

C region genes

xr z

Rearrangement

2. B-cell DNA

(rearranged)

5'_

V2

D2

J5

Transcription

3. Primary RNA transcript

V2

D2

3

Alternative splicing

Translation

Alternative splicing

V2

D2

J5

5. Heavy chain polypeptide

COOH NH2

COOH

Figure 5-2. Heavy (H)-chain synthesis. (1) The variable region of the H chain is coded by three different gene complexes present on chromosome 14: variable (V) region genes, diversity (D) segment genes, and the joining (J) region genes. The constant (C) region gene complex harbors the genes controlling all of the immunoglobulin classes. (2) During rearrangement, a ] region gene links to a D region gene, and then this complex links with a V region gene. The VDJ complex links to the |J. or 8 region genes. (3) A primary RNA transcript of the VDJ(x5 complex is made, and after splicing, mRNAs for a VDJji and a VDJ8 appear (4). H chains of both IgM and IgD result after translation of the mRNAs (5). These H chains combine with light (L) chains and deposit on the B cell membrane as the antigen receptors. Following antigen and cytokine stimulus, the IgM antibody is secreted (not illustrated). (Redrawn with permission from Benjamini E: Immunology : A Short Course, 3rd ed. New York, Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc., 1996, p 100.)

Table 5-1.

Human Leukocyte Antigen (HLA) Classes

Table 5-1.

Human Leukocyte Antigen (HLA) Classes

Complex

HLA

MHC Class

1

II

III

Region

B

C

A

DP

DQ

DR

C4, C2, BF

Gene Products

HLA-B

HLA-C

HLA-A

C' proteins

TNF-a TNF-ß

From IMMUNOLOGY, 3/E by Janis Kuby. ©1992, 1994, and 1997 by W. H. Freeman and Company. Used with permission. MHC = major histocompatibility complex; TNF = tumor necrosis factor.

From IMMUNOLOGY, 3/E by Janis Kuby. ©1992, 1994, and 1997 by W. H. Freeman and Company. Used with permission. MHC = major histocompatibility complex; TNF = tumor necrosis factor.

B. Classes of HLAs. HLAs are organized into three classes of molecules (Table 5-1).

1. Class I HLAs are glycoproteins that are found on the membranes of most nucleated cells.

a. Gene regions. Class I molecules are encoded by three gene regions: A, B, and C.

b. Function. Class I molecules are linked to the cytotoxic T (Tc) cell through the CD8 molecule and present peptidic epitopes to specific Tc receptors (class I restriction). A single class I molecule can bind several different epitopes.

C. Structure (Figure 5-3)

(1) Two chains form the class I molecule.

(a) The a chain has three external domains, a transmembrane segment, and a cytoplasmic tail.

(b) The (^-microglobulin is an invariant protein.

(2) The peptide-binding site, found between domains al and oc2, binds peptides containing 8—10 amino acids.

2. Class II HLAs are glycoproteins that are found on the membranes of dendritic cells, macrophages, and activated T cells and B cells.

a. Gene regions. Class II molecules are encoded by three gene regions: DP, DQ, and DR.

b. Function. Class II molecules are linked to the T helper (Th) cell through the CD4 molecule and present peptidic epitopes to specific Th cell receptors (class II restriction). A single class II molecule can bind several different epitopes.

C. Structure (see Figure 5-3)

(1) Two chains, a and (3, form the class II HLA molecule. Each chain has two domains plus a transmembrane segment and cytoplasmic tail.

(2) The peptide-binding site, formed by juxtaposition of the al and (31 domains, binds peptides containing 13-18 amino acids.

3. Class III HLAs control certain serum proteins, including several complement components and tumor necrosis factors (TNFs). Class III molecules are encoded by three gene regions: C4, C2, and BF.

C. Polymorphism

1. Alleles. Many alleles of class I and II molecules are present at each locus on chromosome 6 and are the major obstacles to organ transplantation.

2. Haplotypes from both parents are inherited and expressed codominantly.

Plasma

A. Class I HLA molecule B. Class II HLA molecule

Peptide-binding site

CX Chain

(3 Chain

CxChain

binding site

Peptide-binding site

CX Chain

(3 Chain

CxChain

binding site

Figure 5-3. Structure of class I and class II human leukocyte antigen (HLA) molecules. —SS— = disulfide bond. (Redrawn with permission from Stites DP, Terr AI, Parslow TG: Medical Immunology, 9th ed. Stamford, CT, Appleton & Lange, 1997, p 86.)

Figure 5-3. Structure of class I and class II human leukocyte antigen (HLA) molecules. —SS— = disulfide bond. (Redrawn with permission from Stites DP, Terr AI, Parslow TG: Medical Immunology, 9th ed. Stamford, CT, Appleton & Lange, 1997, p 86.)

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