MHC and Disease Susceptibility

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Some HLA alleles occur at a much higher frequency in those suffering from certain diseases than in the general population. The diseases associated with particular MHC alleles include autoimmune disorders, certain viral diseases, disorders of the complement system, some neurologic disorders, and several different allergies. The association between HLA alleles and a given disease may be quantified by determining the frequency of the HLA alleles expressed by individuals afflicted with the disease, then comparing these data with the frequency of the same alleles in the general population. Such a comparison allows calculation of relative risk (see Table 7-4). A relative risk value of 1 means that the HLA allele is expressed with the same frequency in the patient and general populations, indicating that the allele confers no increased risk for the disease. A relative risk value substantially

TABLE 7-4l Some significant associations

of HLA alleles with increased risk for various



Associated HLA allele

Relative r

Ankylosing spondylitis



Goodpasture's syndrome



Gluten-sensitive enteropathy



Hereditary hemochromatosis







Insulin-dependent diabetes mellitus



Multiple sclerosis



Myasthenia gravis






Reactive arthritis (Yersinia, Salmonella, Gonococcus)



Reiter's syndrome



Rheumatoid arthritis



Sjogren's syndrome



Systemic lupus erythematosus



"Relative risk is calculated by dividing the frequency of the HLA allele in the patient population by the frequency in the general population:

"Relative risk is calculated by dividing the frequency of the HLA allele in the patient population by the frequency in the general population:

SOURCE: Data from SAM CD: A Comprehensive Knowledge Base of Internal Medicine, D. C. Dale and D. D. Federman, eds., 1997, Scientific American, New York.



HFE and Hereditary Hemochromatosis

Hereditary hemochromatosis (HH) is a disease in which defective regulation of dietary iron absorption leads to increased levels of iron. HH (which in earlier reports may be referred to as idiopathic or primary hemochromatosis) is the most common known autosomal recessive genetic disorder in North Americans of European descent, with a frequency of 3-4 cases per 1000 persons. Recent studies show that this disease is associated with a mutation in the nonclassical class I gene HFE (formerly designated HLA-H), which lies to the telomeric side of HLA-A. The association of the HFE gene with HH is an example of how potentially life-saving clinical information can be obtained by studying the connection of HLA genes with disease.

The total iron content of a normal human adult is 3 to 4 grams; the average dietary intake of iron is about 10 to 20

milligrams per day; of this, only 1 to 2 mg is absorbed. The iron balance is maintained by control ofits absorption from digested food in the intestinal tract. The primary defect in H H is increased gastrointestinal uptake ofiron and, as a result of this, patients with HH may throughout their lives accumulate 15 to 35 grams of iron instead of the normal 3 to 4 grams. The iron overload results in pathologic accumulation of iron in cells of many organs, including the heart and liver. Although a severe form of HH may result in heart disease in children, the clinical manifestations of the disease are not usually seen until 40 to 50 years of age. Males are affected eight times more frequently than females. Early symptoms of HH are rather nonspecific and include weakness, lethargy, abdominal pain, diabetes, impotence, and severe joint pain. Physical examination of HH sufferers reveals liver damage, skin pigmentation, arthritis, en-

High-magnification iron stain of liver cells from HH patient. The stain confirms the presence of iron in both parenchymal cells (thick arrow) and bile duct cells (thin arrow). This woman with hemochromatosis required removal of 72 units (about 36 liters or 9 gallons) of blood during one and a half years to render her liver free of excess iron. [SAM CD: A Comprehensive Knowledge Base of Internal Medicine, D. C. Dale and D. D. Federman, eds., 1997, Scientific American, New York.]

Marmo Tino

above 1 indicates an association between the HLA allele and the disease. As Table 7-4 shows, individuals with the HLA-B27 allele have a 90 times greater likelihood (relative risk of 90) of developing the autoimmune disease ankylosing spondylitis, an inflammatory disease of vertebral joints characterized by destruction of cartilage, than do individuals with a different HLA-B allele.

The existence of an association between an MHC allele and a disease should not be interpreted to imply that the expression of the allele has caused the disease—the relationship between MHC alleles and development of disease is complex. In the case of ankylosing spondylitis, for example, it has been suggested that because of the close linkage of the TNF-a and TNF-p genes with the HLA-B locus, these cytokines may be involved in the destruction of cartilage. An association of HLA class I genes with the disease hereditary hemochro-matosis is discussed in the Clinical Focus box in this chapter.

When the associations between MHC alleles and disease are weak, reflected by low relative risk values, it is likely that multiple genes influence susceptibility, of which only one is in the MHC. That these diseases are not inherited by simple Mendelian segregation of MHC alleles can be seen in identical twins; both inherit the MHC risk factor, but it is by no means certain that both will develop the disease. This finding suggests that multiple genetic and environmental factors have roles in the development of disease, especially autoimmune diseases, with the MHC playing an important but not exclusive role. An additional difficulty in associating a particular MHC product with disease is the genetic phenomenon of linkage disequilibrium, which was described above. The fact that some of the class I MHC alleles are in linkage disequilibrium with the class II MHC alleles makes their contribution to disease susceptibility appear more pronounced than it actually is. If, for example, DR4 contributes to risk of a disease, and if it occurs frequently in combination with A3 because of linkage disequilibrium, then A3 would incorrectly appear to be associated with the disease. Improved genomic mapping techniques make it possible to analyze the linkage between the MHC and various diseases more fully and to assess the contributions from other loci.

larged spleen, jaundice, and peripheral edema. Ifuntreated, HH results in hepatic cancer, liver failure, severe diabetes, and heart disease. Exactly how the increase in iron content results in these diseases is not known, but repeated phlebotomy (taking blood) is an effective treatment if the disease is recognized before there is extensive damage to organs. Phlebotomy does not reverse damage already done. Phlebotomy (also called blood-letting) was used as treatment for many conditions in former times; HH may be one of the rare instances in which the treatment had a positive rather than a harmful effect on the patient.

Prior to appearance of the recognized signs of the disease, such as the characteristic skin pigmentation or liver dysfunction, diagnosis is difficult unless for some reason (such as family history of the disease) HH is suspected and specific tests for iron metabolism are performed. A reliable genetic test for HH would allow treatment to commence prior to disease manifestation and irreversible organ damage.

Because it is a common disease, the association ofHH with HLA was studied; initially a significant association with the HLA-A3 allele was found (RR of 9.3). This association is well documented, but the relatively high frequency of the HLA-A3 allele (present in 20% of the North American population) makes this an inadequate marker; the majority of individuals with HLA-A3 will not have HH. Further studies showed a greatly increased relative risk in individuals with the combination of HLA-A3 and HLA-Bi4; homozygotes for these two alleles carried a relative risk for HH of 90. Detailed studies of several populations in the US and France with high incidence of HH revealed a mutation in the nonclassi-cal HLA class I gene HFE in 83%-100% of patients with HH. HFE, which lies close to the HLA-A locus, was shown in several independent studies to carry a characteristic mutation at position 283 in HH patients, with substitution of a tyrosine residue for the cysteine normally found at this position. The substitution precludes formation of the disulfide link between cysteines in the a3 domain, which is necessary for association of the MHC a chain with ^-microglobulin and for expression on the cell surface. HFE molecules are normally expressed on the surface of cells in the stomach, intestines, and liver. There is evidence showing that HFE plays a role in the abil ity ofthese organs to regulate iron uptake from the circulation. The mechanism by which HFE functions involves binding to the transferrin receptor, which reduces the affinity of the receptor for iron-loaded transferrin. This lowers the uptake of iron by the cell. Mutations that interfere with the ability of HFE to form a complex with transferrin and its receptor can lead to increased iron absorption and HH.

There are several possible reasons for why this defect continues to be so common in our population. Factors that favor the spread of the defective HFE gene would include the fact that it is a recessive trait, so only homozygotes are affected; the gene is silent in carriers. In addition, even in most homozygotes affected with HH, the disease does not manifest itself until later in life and so may have minimal influence on the breeding success of the HH sufferer.

Studies of knockout mice that lack the gene for ^-microglobulin demonstrate that MHC class I products on cell surfaces are necessary for the maintenance of normal iron metabolism. These mice, which are unable to express any of their class I molecules on the cell surfaces, suffer from iron overload with disease consequences similar to HH.

A number of hypotheses have been offered to account for the role of the MHC in disease susceptibility. As noted earlier, allelic differences may yield differences in immune responsiveness arising from variation in the ability to present processed antigen or the ability of T cells to recognize presented antigen. Allelic forms of MHC genes may also encode molecules that are recognized as receptors by viruses or bacterial toxins. As will be explained in Chapter 16, the genetic analysis of disease must consider the possibility that genes at multiple loci may be involved and that complex interactions among them may be needed to trigger disease.

Some evidence suggests that a reduction in MHC polymorphism within a species may predispose that species to infectious disease. Cheetahs and certain other wild cats, such as Florida panthers, that have been shown to be highly susceptible to viral disease have very limited MHC polymorphism. It is postulated that the present cheetah population (Figure 7-17) arose from a limited breeding stock, causing a loss of MHC diversity. The increased susceptibility of cheetahs to various viral diseases may result from a reduction in

Cheetah Mhc Polymorphism

Cheetah female with two nearly full grown cubs. Polymorphism in MHC genes of the cheetah is very limited, presumably because of a bottleneck in breeding that occurred in the not too distant past. It is assumed that all cheetahs alive today are descendants of a very small breeding pool. [Photograph taken in the Oka-vango Delta, Botswana, by T. J. Kindt.]

the number of different MHC molecules available to the species as a whole and a corresponding limitation on the range of processed antigens with which these MHC molecules can interact. Thus, the high level of MHC polymorphism that has been observed in various species may provide the advantage of a broad range of antigen-presenting MHC molecules. Although some individuals within a species probably will not be able to develop an immune response to any given pathogen and therefore will be susceptible to infection by it, extreme polymorphism ensures that at least some members of a species will be able to respond and will be resistant. In this way, MHC diversity appears to protect a species from a wide range of infectious diseases.


■ The major histocompatibility complex (MHC) comprises a stretch of tightly linked genes that encode proteins associated with intercellular recognition and antigen presentation to T lymphocytes.

■ A group of linked MHC genes is generally inherited as a unit from parents; these linked groups are called haplo-types.

■ MHC genes are polymorphic in that there are large numbers of alleles for each gene, and they are polygenic in that there are a number of different MHC genes.

■ Class I MHC molecules consist of a large glycoprotein chain with 3 extracellular domains and a transmembrane segment, and ^-microglobulin, a protein with a single domain.

■ Class II MHC molecules are composed of two noncova-lently associated glycoproteins, the a and p chain, encoded by separate MHC genes.

■ X-ray crystallographic analyses reveal peptide-binding clefts in the membrane-distal regions of both class I and class II MHC molecules.

■ Both class I and class II MHC molecules present antigen to T cells. Class I molecules present processed endogenous antigen to CD8 T cells. Class II molecules present processed exogenous antigen to CD4 T cells.

■ Certain conserved motifs in peptides influence their ability to interact with the membrane-distal regions of class I and class II MHC molecules.

■ Class I molecules are expressed on most nucleated cells; class II antigens are restricted to B cells, macrophages, and dendritic cells.

■ The class III region of the MHC encodes molecules that include a diverse group of proteins that play no role in antigen presentation.

■ Detailed maps of the human and mouse MHC reveal the presence of genes involved in antigen processing, including proteasomes and transporters. ^^ Self-Test Review and quiz of key terms

■ Studies with mouse strains have shown that MHC haplo-type influences immune responsiveness and the ability to present antigen.

■ Increased susceptibility to a number of diseases, predominantly, but not exclusively, of an autoimmune nature, has been linked to certain MHC alleles.

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  • sabine
    Why would a loss of MHC class I result in an increased susceptibility to viral infections?
    7 months ago
  • Sabine
    How are particular mhc alleles associated with increased susceptibility to certain diseases?
    6 months ago
  • steve yearby
    What are some of the mechanisms that result in the mhc polymorphism we see in individuals?
    1 month ago

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