R

DNA (active gene)

Y Primary RNA transcript

Translation

Figure 16.22 Antibody Diversity Immunoglobulin (IgG) gene arrangement in an immature lymphocyte and the mechanism of active gene formation. Only the heavy chain is shown.

Chapter 16 The Adaptive Immune Response

PERSPECTIVE 16.1 What Flavor Are Your Major Histocompatibility Complex Molecules?

Set of MHC genes inherited from your mother:

HLA-B HLA-C HLA-A

Set of MHC genes inherited from your mother:

HLA-B HLA-C HLA-A

One of at least 464 One of at least 111 One of at least 229

different alleles different alleles different alleles

One of at least 464 One of at least 111 One of at least 229

different alleles different alleles different alleles

Set of MHC genes inherited from your father:

HLA-B HLA-C HLA-A

Set of MHC genes inherited from your father:

HLA-B HLA-C HLA-A

One of at least 464 One of at least 111 One of at least 229

different alleles different alleles different alleles

Figure 1 MHC Polymorphisms The order of the MHC class I genes on the chromosome is B, C, and A.

One of at least 464 One of at least 111 One of at least 229

different alleles different alleles different alleles

Figure 1 MHC Polymorphisms The order of the MHC class I genes on the chromosome is B, C, and A.

The major histocompatibility molecules were discovered over half a century ago, long before their critical role in adaptive immunity was recognized. During World War II, bombing raids caused serious burns in many people, stimulating research into the transplantation of skin to replace burned tissue.This research quickly spread to the study of transplantation of a variety of other tissues and organs, including bone marrow, which contains the stem cell precursors of all blood cells in the body. Such transplants were readily rejected, however, due to certain cell surface molecules that differed between tissue donor and recipient.The immune system of the transplant recipient recognized the molecules as foreign and made a vigorous response, resulting in the rejection of the tissue. This led to the development of tissue-typing tests that enabled researchers to more closely match donor and recipient tissues.The typing tests exploit surface structures on leukocytes that serve as markers for tissue compatibility; the structures were called human leukocyte antigens or HLAs. Later, researchers determined that HLAs were encoded by a cluster of genes, now called the major histocompatibility complex. Unfortunately, the terminology can be confusing because the molecules that transplant biologists refer to as HLAs are called MHC molecules by immunologists.

It is highly unlikely that two random individuals will have identical MHC molecules.This is because the genes encoding them are polygenic, meaning they are encoded by more than one locus, or position on the chromosome, and each locus is highly polymorphic, meaning there are multiple variations (figure 1). There are three loci of MHC class I genes, designated HLA-A, HLA-B, and HLA-C; in other words, if MHC molecules were candy, each cell would be covered with pieces of chocolate (HLA-A), taffy (HLA-B), and lollipop (HLA-Q.There are more than 100 different alleles, or forms, of each of the three genes. Continuing with the candy analogy, the flavor at the chocolate locus could be dark, white, or milk chocolate; the taffy could be peppermint or cinnamon, and so on.The list of known alleles continues to increase, but currently there are at least 229 alleles for HLA-A, 464 for HLA-B, and 111 for HLA-C. In addition, all of the loci are co-dominantly expressed. In other words, you inherited one set of the three genes from your mother and one set from your father; both sets are expressed. Putting this all together, and assuming that you inherited two completely different sets of alleles from your parents, your cells express six different MHC class I molecules—two of the over 229 known HLA-A possibilities, two of the over 464 HLA-B possibilities, and two of the over 111 HLA-C possibilities. As you can imagine, the likelihood that any person you encounter in a day will have those same MHC class I molecules is extremely unlikely, unless you have an identical twin.

Why is there so much diversity in MHC molecules? The answer lies in the complex demands of antigen presentation. MHC class I molecules bind peptides that are only 8 to 10 amino acids in length; MHC class II molecules bind peptides that are only 13 to 25 amino acids in length. Somehow, within that constraint, the MHC molecules must bind as many different peptides as possible in order to ensure that a representative selection from the proteins within a cell can be presented to T cells.The ability to bind a wide variety of peptides is particularly important considering how readily viruses and bacteria can evolve in response to selective pressure. For example, if a single alteration in a viral protein prevented all MHC molecules from presenting peptides from that protein, then a virus with that mutation could routinely overwhelm the body. The ability to bind different peptides is not enough, however, because, ideally, a given peptide should be presented in several slightly different orientations so that distinct aspects of the three-dimensional structures can be inspected by T-cell receptors. No single variety of MHC molecules can accomplish all of these aims, which probably accounts for the diversity in MHC molecules.

The variety of MHC molecules that a person has on his or her cells impacts that individual's adaptive response to certain antigens.This is not surprising since MHC molecules differ in the array of peptides they can bind and manner in which those peptides are held in the molecule.Thus, they impact what the T cells actually "see." In fact, the severity of certain diseases has been shown to correlate with the MHC type of the infected individual. For example, rheumatic fever, which can occur as a consequence of Streptococcus pyogenes infection, develops more frequently in individuals with certain MHC types.The most serious manifestations of schistosomiasis have also been shown to correlate with certain MHC types. Epidemics of life-threatening diseases such as plague and smallpox have dramatically altered the relative proportion of MHC types in certain populations, killing those whose MHC types ineffectively present peptides from the causative agent. ■ rheumatic fever, p. 567 ■ schistosomiasis, p. 388

After a developing B cell begins producing a functional B-cell receptor, it is then exposed to various other cells and material in the bone marrow. Because the bone marrow is normally free of foreign substances, any B cell that binds material there must be recognizing "self" and therefore ought to be eliminated. This occurs by inducing the cell to undergo apoptosis.

Negative selection also occurs in secondary lymphoid organs. Any naive B cell that recognizes antigen but does not receive agreement from an activated T-helper cell is rendered unresponsive and eventually undergoes apoptosis. This process eliminates cells that recognize antigens not associated with threat or destruction, a critical aspect of the body's ability to discriminate between "danger" and "harmless."

Positive and Negative Selection of Self-Reactive T Cells

Developing T cells have two phases of trials—positive and negative selection—that seal their fate. Positive selection is a process that permits only those T cells that recognize MHC to some extent to develop further. Recall that the T-cell receptor, unlike the B-cell receptor, recognizes a peptide:MHC complex. T cells, therefore, must show at least some recognition of the MHC molecules regardless of the peptide they are carrying. T cells that show insufficient recognition fail positive selection and, as a consequence, are eliminated. Each T cell that passes positive selection is also subjected to negative selection, analogous to that which occurs during B cell development. T cells that recognize

"self" peptides presented by MHC molecules are eliminated. Positive and negative selection processes are so stringent that over 95% of developing T cells undergo apoptosis in the thymus.

As occurs with B cells, negative selection also occurs in the secondary lymphoid organs. Any naive T cell that recognizes antigen presented by an antigen-presenting cell not expressing co-stimulatory molecules is eliminated.

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