Adaptive Immunity: Histocompatibility Antigens and Immune Response Genes Part 2

Clonal selection of t cells

The corecognition of MHC and peptide fragments of an antigen bound in the groove of the class I or class II molecules appears to require that the binding surface of the TCR and the binding surface formed by MHC plus peptide be attached at multiple points [see 6:111 Adaptive Immunity: Antigens, Antibodies, and T Cell and B Cell Receptors]. Each T cell clone is specific for a self-MHC-peptide complex and generally does not have sufficient affinity for MHC or peptide to bind well to either component alone. There is extensive evidence that the development of the T cell repertoire in the thymus begins during the fetal period and continues well into adult life as new precursor cells from the bone marrow mature in the thymus. In this process, many potential clones are destroyed and others are selected to mature. The selected T cell clones then leave to populate the rest of the body. The MHC of the host plays the major role in selection: T cell clones that are strongly autoreactive to self-MHC molecules are eliminated, leaving clones with weak affinity to self-MHC to survive. Because the surviving clones have a large variety of T cell receptor rearrangements [see 6:111 Adaptive Immunity: Antigens, Antibodies, and T Cell and B Cell Receptors], the individual retains the necessary repertoire of T cell clones that can recognize self-MHC plus peptide. The successful crystallization of a complex consisting of a human TCR, its viral peptide, and the HLA-A2 molecule that binds it has revealed the configuration and extent of the binding surface between the TCR and the MHC-pep-tide surface. The axis of the TCR is diagonal to that of the MHC helices, so that it covers a large portion of both a helices and the peptide between them. Although the extensive MHC polymorphisms increase the likelihood that a particular peptide fragment will be bound so that it can be recognized by T cells, a given individual has a small repertoire of such MHC binding sites compared with the rich combinatorial possibilities in the TCR gene complex. The inheritance of multiple HLA loci from two parents, however, increases the potential for recognizing a greater number of different self-MHC-peptide complexes and therefore increases the likelihood that at least some persons will survive a given infection.

The alloresponse, which is the immune response mounted against another individual’s cells, is a special case. Except for direct activation of T cell subsets with bacterial superantigens (e.g., staphylococcal exotoxins), the in vitro proliferation of T cells in the MLR is the most vigorous antigen-specific response known because it does not require the priming that is needed to induce proliferation to microbial antigens. Transplantation is, of course, a technological artifact and would not have been encountered during evolution; only pregnancy has the potential for exposing the cells of one person to those of another having different HLA haplotypes. The allobarrier could have made pregnancy difficult or impossible except for the presence of several imperfectly defined mechanisms at the placental level that protect the fetus from rejection. The existence of such mechanisms suggests that the need for MHC polymorphisms is most important and requires special protection at the maternal-fetal interface.

Alloreactive T cells are known to either indirectly perceive allo-MHC peptides presented on self-MHC molecules or directly recognize intact allo-MHC molecules that hold a self-peptide.13 Because a number of peptides derived from endogenous proteins occupy MHC binding sites at all times, such self-peptides need not be polymorphic or unique to an individual. The functional significance of the indirect, as well as the direct, pathways in transplantation has been established. It has been shown in animal models that immunization with synthetic allopeptides alone can cause accelerated graft rejection,14,15 whereas administration of such peptides by the oral or intrathymic route can increase tolerance for alloantigens. Also, priming to allopeptides presented by self-MHC molecules is a feature of rejection activity in human transplant recipients.

Generation of cytotoxic t cells

The MLR leading to the generation of cytotoxic T cells requires two distinct types of responding T cells. The process begins with the stimulating cell—a B cell, dendritic cell, or monocyte—which has both MHC class I and MHC class II molecules on its surface. The class II molecule stimulates subsets of responding T cells to proliferate and become helper T cells. This subset is marked by the CD4 antigen. The class I molecule sensitizes a second subset of T cells, which become cytotoxic T cells if stimulated by the proliferating helper T cells. One of these stimulatory signals is mediated by the lymphokine interleukin-2 (IL-2). This second T cell subset is marked by the CD8 antigen. Cytotoxic T cells that develop against cells that differ only in their class II antigens bear the CD4 marker. The two stimuli—the one that induces helper T cell proliferation and the one that sensitizes T cells to become cytotox-ic—can be delivered by different cells [see Table 2]. This type of cell interaction and cooperation is thought to mirror in vivo events that lead to graft rejection by cytotoxic T cells, showing why it is desirable to have both class I antigen and class II antigen compatibility between donor and recipient cells.

It was formerly thought that CD4+ T cells were simply helper lymphocytes and that CD8+ T cells were either cytotoxic or suppressor lymphocytes, but these functional divisions do not appear to be clear-cut. Ongoing molecular studies indicate that the CD4 surface molecule is closely associated with the TCR and guides interaction between T cells and antigen-presenting cells by binding to a nonpolymorphic region of MHC class II molecules [see 6:III Adaptive Immunity: Antigens, Antibodies, and T Cell and B Cell Receptors]. Similarly, the CD8 molecule binds to MHC class I molecules on antigen-presenting cells. CD4 and CD8 molecules also increase the strength with which the TCR complex binds to the antigen-MHC complex. In addition, these surface molecules participate in signaling activation of the adherent T cell.

Immune Response Genes

As previously mentioned, many lines of evidence indicate that MHC class II molecules are the expressed products of immune response (Ir) genes; in other words, immune responsiveness can be a direct function of antigen presentation. If an antigen fragment is not bound to a class II molecule, a person’s immune system is unable to recognize it. Certain diseases in animals—including virally induced forms of leukemia, mammary tumors, and lymphocytic choriomeningitis—have been linked to polymorphism of MHC class II genes. However, the ability of specific HLA antigens to confer susceptibility to clinically important infectious agents has rarely been suggested (see below). It is likely that evolution has resulted in selection of MHC alleles that are capable of binding at least some portions of antigenic molecules on infectious agents. In addition, the duplication of class II genes with expression of HLA-DR, HLA-DQ, and HLA-DP sets of molecules increases the likelihood that a response can be initiated in a given case. In particular, polymorphisms on both a and p chains of HLA-DQ and HLA-DP provide considerable variation in binding configurations, especially when a| dimers are composed of chains inherited from both parents; for example, amother/ |father may provide a peptide-bind-ing molecule not present in either parent. There are also many non-MHC influences on immune responsiveness; none of these have yet been well characterized clinically.

Table 3 Diseases Showing Positive HLA Antigen Association(s)²²

Type	Disease	Serologic HLA Antigen	Relative Risk*
	Ankylosing spondylitis	B27	90.0
	Reiter syndrome	B27	37.0
	Acute anterior uveitis	B27	8.2
	Reactive arthritis	B27	18.0
	Psoriatic arthritis	B27	10.7
		B38	9.1
	Juvenile rheumatoid arthritis	B27	3.9
	Juvenile rheumatoid arthritis (pauciarticular)	DR5	3.3
	Rheumatoid arthritis	DR4/Dw4	6.0
	Sjogren syndrome	Dw3	10.0
	Systemic lupus erythematosus	DR3	2.6
	Gluten-sensitive enteropathy	DR3	12.0
	Chronic active hepatitis	DR3	6.8
	Ulcerative colitis	B5	3.8
	IgA deficiency	DR3	13.0
	Idiopathic hemochromatosis	A3	6.7
		B14	2.7
		A3, B14	90.0
	Pernicious anemia	DR5	5.0
	Hodgkin disease	DP3	2.0
	Dermatitis herpetiformis	DR3	17.3
	Psoriasis vulgaris	Cw3	7.5
	Psoriasis vulgaris (Japanese)	Cw6	8.5
	Pemphigus vulgaris (Jewish)	DR4	24.0
	Behcet disease (white)	A26 B5	4.8 3.8
	Behcet disease (Japanese)	B51	12.4
	Diabetes mellitus, type 1	DR4	6-7
		DR3	5.0
		DR2	0.25
		BfF1+	15.0
	Graves disease	B8	2.5
		DR3	3.7
	Graves disease (Japanese)	B35	4.4
		DR3	3.7
	Addison disease	Dw3	10.5
	Subacute thyroiditis	B35	13.7
	Hashimoto thyroiditis	DR5	3.0
	Congenital adrenal hyperplasia	B47	15.4
	Myasthenia gravis	B8	3.0
	Multiple sclerosis	DR2/Dw2	6.0
	Narcolepsy	DR2, DQ6	130.0
	Bipolar disorder	B16	2.3
	Schizophrenia	A28	2.3
	Idiopathic membranous nephropathy	DR3	5.7
	Goodpasture syndrome	DR2	16.0
	Minimal change disease	DR7	4.2
	IgA nephropathy (French, Japanese)	DR4	3.1
	Gold/penicillamine nephropathy	DR3	14.0
	Polycystic kidney disease	B5	2.6
	Tuberculoid leprosy (Asians)	B8	6.8
	Paralytic polio	B16	4.3
	Low versus high response vaccinia	Cw3	12.7
	Falciparum malaria, severe	B53	0.4-0.5

Studies in humans have also suggested the ability of the MHC to suppress immunologic responses to environmental agents, such as streptococcal infection, schistosomiasis, and leprosy, as well as antigens from cedar pollen and hepatitis B vaccine. For example, the in vitro IgE response to cedar pollen antigen is suppressed by T cells of persons bearing HLA-DQ3, but the mechanisms of such T cell-mediated suppression are ill defined.17,18

Complement factor genes

Several complement proteins are encoded by genes that are linked to the MHC. These proteins include C2 and factor B (Bf), which are closely linked and also similar in structure, suggesting gene duplication. In addition, two loci for C4 (C4A and C4B) are closely linked to C2 and Bf. The C2 deficiency associated with systemic lupus erythematosus is associated with the HLA-A25, B18 haplotype. Indeed, researchers have found extended haplo-types in which the same HLA-B, HLA-DR, HLA-DQ, and complement types are found in apparently unrelated persons with the same disease. These circumstances could result from a mutation occurring in a common ancestor. Alternatively, there may be selective pressures to keep in close proximity genes that produce proteins that act together.

Nonimmunologic functions of mhc genes

MHC genes are possibly also important in a variety of nonim-munologic cell-cell interactions. In 1976, a study showed that when a male mouse was presented with two females in estrus that were genetically identical except in portions of the MHC, the male would most often choose to mate with the female of an MHC type different from his own.19 Further experiments showed that the male discriminated between MHC types by sense of smell. The advantage most apparent in this example of opposites attracting is that the heterozygosity of genes in the region that encodes for MHC ensures a wider range of immune defenses for the hybrid progeny of such matings. There is no evidence that humans can sense HLA antigens, however.

Disease and the Major Histocompatibility Complex

Hla-associated disease

Many diseases have been associated with certain MHC antigens [see Table 3]. Such associations per se show only that the MHC molecules or some other genes closely linked in the HLA region have an influence on initiation or expression of disease. A relative risk of 5, for example, means only that there is a fivefold increase in the likelihood of disease in a person with a particular HLA antigen, compared with someone who does not have that antigen. It indicates nothing about the frequency of the disease itself, which may be rare or common. One explanation for such associations is that the disease in question is related to a deficiency in the immune response to a particular causative organism. There is increasing evidence, however, that organ-specific HLA-associated diseases—such as type 1 diabetes mellitus, multiple sclerosis, Graves disease, the glomerulonephritides, celiac disease, ankylosing spondylitis, and rheumatoid arthritis—have a major component of autoimmunity.

In animal models in which appropriate breeding studies have been done, it has been demonstrated that autoimmune states depend on five to 15 randomly segregating genes, one of which is in the MHC. Polygenic etiology of human autoimmunity is very likely, and the HLA components may be useful targets for intervention, particularly in diseases in which HLA presentation of an immunogenic self-peptide is a key event. Also, with the development of inflammation, de novo expression of HLA class II molecules on tissue cells may provide the immune stimulus for perpetuation of the autoimmune process. For example, patients with thyroiditis show aberrant expression of HLA-DR on thyroid cells, providing a possible mechanism by which thyroid antigen could be presented to T cells.

There has been some progress in discerning which diseases may be directly related to immunogenic peptide presentation. Analysis of the sequences of genes encoding MHC class II molecules from patients with type 1 diabetes mellitus suggests that inheritance of particular HLA alleles is important in determining susceptibility to this disease, involving a T cell-mediated autoimmune response to pancreatic islet cell antigens. Resistance to type 1 diabetes mellitus is strongly associated with the presence of as-partate at position 57 of the HLA-DQB chain. In persons with the HLA-DR2 haplotype, for example, the relative risk for the disease drops to 0.2 [see Table 3]. HLA-DR2 is in linkage disequilibrium with HLA-DQB alleles, such as DQB1*0602, encoding aspartate at position 57. In contrast, when aspartate is not present at position 57, particularly in persons with the HLA-DR3 or HLA-DR4 haplo-type, there is an increased risk of type 1 diabetes mellitus. Amino acid residue 57 on the HLA-DQB chain would lie toward one end of the groove; aspartate at that position may influence binding of a peptide to this class II molecule, causing reduction of helper T cell responses or activation of suppressor T cell responses to pancreatic islet cell antigens. Many studies in certain ethnic groups have shown that the greatest susceptibility to type 1 diabetes mel-litus is related to HLA-DQ. The DQA/DQB heterodimer DQA1*0301/DQB1*0201 is associated with the highest risk. What is of interest here is that this heterodimer is uncommon, occurring mostly in persons who have inherited the DQA gene from one parent and the DQB from the other. Whereas DQA1*0301 and DQB1*0201, usually found with DR4 and DR3 haplotypes, respectively, separately increase the risk for type 1 diabetes mellitus, together they provide the highest risk of disease. As noted previously, the formation of a heterodimer from the products of genes inherited from both parents does occur with the HLA-DQ molecule. The hypothesis is that this "new" peptide-binding site will be most effective in the presentation of pancreatic islet cell autoanti-gen. Definition of the binding motifs of this site may provide a clue to the antigen. There are additional and independent effects of HLA-DR—particularly the DR4 alleles, some of which are associated with enhancement and others with suppression of the risk for diabetes. Amino acid differences in the hypervariable regions of MHC class II molecules have also been associated with such autoimmune disorders as pemphigus vulgaris and rheumatoid arthritis.

The association of narcolepsy with HLA-DR2 (DRB1*1501) is more than 90%, but the highest association is with HLA-DQA1*0102/DQB1*0602. The HLA effect is dominant, not recessive, and there is no indication of an immunologic defect in affected persons. An abnormality in a peptide neurotransmitter or its receptor has been postulated, but the relation to the HLA-D-region genes remains elusive.

About 80% to 90% of celiac disease is associated with HLA-DQA1*0501/DQB1*0201. The peptide-binding groove of this  molecule is known to bind a peptide of wheat protein gliadin, which is a potentiating if not etiologic factor in this disease.

Although an HLA molecule may determine specificity to a particular autoantigen, it is possible that genes controlling other factors (e.g., the production of antigen receptors, specific subsets of regulatory cells, or helper and suppressor molecules) are responsible for a general tendency toward an abnormal immune response. Additional study of the peculiar role of the HLA system in autoimmunity may well reveal mechanisms of autoimmune disease that are currently unknown.