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The HLA System The New England Journal of Medicine Review Articles Advances in Immunology plasmic tail (Fig. 2). There are some 20 class I genes in the HLA region; three of these, HLA-A, B, and C, the so-called classic, or class Ia genes, are the main I AN MACKAY, M.D., AND FRED S. ROSEN, M.D., actors in the immunologic theater. Editors The class II genes code for the a and b polypeptide chains of the class II molecules (Fig. 2). The desig- nation of their loci on chromosome 6 consists of three THE HLA SYSTEM letters: the first (D) indicates the class, the second (M, O, P, Q, or R) the family, and the third (A or B) First of Two Parts the chain (a or b, respectively). HLA-DRB, for ex- ample, stands for class II genes of the R family cod- JAN KLEIN, PH.D., AND AKIE SATO, PH.D. ing for the b chains. The individual genes of the HLA system are differentiated by Arabic numbers, and the notation for the numerous allelic variants of these MAN dies because his body has rejected a genes is a number preceded by an asterisk. For ex- heart transplant; a woman is crippled by rheu- ample, HLA-DRB1*0401 stands for allelic variant A matoid arthritis; a child goes into a coma that 0401 of gene 1, which encodes the b chain of a class is brought on by cerebral malaria; another child dies II molecule belonging to the R family. Each of the of an infection because of an immunodeficiency; an class II a and b chains has four domains: the pep- elderly man has advanced hepatic cirrhosis caused by tide-binding domain (a1 or b1), the immunoglobu- iron overload. These five clinical situations are as di- lin-like domain (a2 or b2), the transmembrane re- verse as can be, yet all have one thing in common: the gion, and the cytoplasmic tail (Fig. 2). cause of all of them involves the human leukocyte an- Class I genes are expressed by most somatic cells, tigen (HLA) system, the human version of the major although the level of expression varies depending on histocompatibility complex (MHC). Malfunction of the tissue.1 By contrast, class II genes are normally ex- the HLA system, which is at the root of these and pressed by a subgroup of immune cells that includes many other clinical disorders, has such wide-ranging B cells, activated T cells, macrophages, dendritic cells, effects not only because of the system’s role in the and thymic epithelial cells.1 In the presence of inter- adaptive immune response, but also because of its feron-g, however, other types of cells can express genetic complexity. class II HLA molecules. The function of both class The HLA complex on chromosome 6 contains over I and class II molecules is the presentation of short, 200 genes, more than 40 of which encode leukocyte pathogen-derived peptides to T cells, a process that antigens (Fig. 1).1-3 The rest are an assortment of genes initiates the adaptive immune response. To under- that are not evolutionarily related to the HLA genes stand this function, it is necessary to place it in the themselves, although some are involved with them context of the cell’s physiology, in particular the proc- functionally.4 Many genes within this complex have ess of waste disposal. nothing to do with immunity. The HLA genes that ANTIGEN PROCESSING are involved in the immune response fall into two AND PRESENTATION classes, I and II, which are structurally and function- ally different (Fig. 2). The class I genes code for the Cells are equipped with an enviably clean and ef- a polypeptide chain of the class I molecule; the ficient system of waste disposal and recycling. A spe- b chain of the class I molecule is encoded by a gene cial molecule, ubiquitin, marks worn-out proteins for dumping (Fig. 3A). These proteins unfold with the on chromosome 15, the beta2-microglobulin gene. The a chain has five domains: two peptide-binding help of other specialized molecules, the chaperones, domains (a1 and a2), one immunoglobulin-like do- and the polypeptide chains are then fed into barrel- main (a3), the transmembrane region, and the cyto- shaped structures, the proteasomes, which chop them up into short fragments.5 The peptides emerging from the proteasome are either degraded into amino acids in the cytosol or transferred into the endoplasmic From the Max-Planck-Institut für Biologie, Abteilung Immungenetik, reticulum. Tübingen, Germany. Address reprint requests to Dr. Klein at the Max-Planck- Extracellular proteins take a different route to deg- Institut für Biologie, Abteilung Immungenetik, Corrensstr. 42, D-72076 Tübingen, Germany, or at [email protected]. radation (Fig. 3B). They are herded into small bags ©2000, Massachusetts Medical Society. that invaginate from the plasma membrane into the 702 · September 7, 2000 The New England Journal of Medicine Downloaded from nejm.org at UC SHARED JOURNAL COLLECTION on May 26, 2011. For personal use only. No other uses without permission. Copyright © 2000 Massachusetts Medical Society. All rights reserved. ADVANCES IN IMMUNOLOGY Chromosome 6 q Centromere p Telomere Telomere Regions 6p21.31 Class II Class III Class I HLA class II% region loci TAPBP PSMB9 (LMP2) TAP1 PSMB8 (LMP1) TAP2 DPB2 DPB1 DPA1 DOA DMA DMB DOB DQB1 DQA1 DRB1 DRB2 DRB3 DRA HLA class III% region loci C21B , a- C4B C4A BF C2 HSPA1B HSPA1A HSPA1L LTB TNF- LTA P450 HLA class I % region loci MICB MICA HLA-B HLA-C HLA-E HLA-A HLA-G HLA-F HFE Figure 1. Location and Organization of the HLA Complex on Chromosome 6. The complex is conventionally divided into three regions: I, II, and III. Each region contains numerous loci (genes), only some of which are shown. Of the class I and II genes, only the expressed genes are depicted. Class III genes are not related to class I and class II genes structurally or functionally. BF denotes complement factor B; C2 complement component 2; C21B cytochrome P-450, subfamily XXI; C4A and C4B complement components 4A and 4B, respectively; HFE hemochromatosis; HSP heat-shock protein; LMP large multifunctional protease; LTA and LTB lymphotoxins A and B, respectively; MICA and MICB major-histocompatibility- complex class I chain genes A and B, respectively; P450 cytochrome P-450; PSMB8 and 9 proteasome b 8 and 9, respectively; TAP1 and TAP2 transporter associated with antigen processing 1 and 2, respectively; TAPBP TAP-binding protein (tapasin); TNF-a tumor necrosis factor a; and HSPA1A, HSPA1B, and HSPA1L heat-shock protein 1A A-type, heat-shock protein 1A B-type, and heat-shock protein 1A–like, respectively. cytoplasm. The bags are then pinched off as endocyt- originating from the pathogen are also routed into ic vesicles, and they fuse with primary lysosomes, the processing pathways. With the exception of jawed which are loaded with an assortment of proteolytic vertebrates, no organisms appear to make a distinction enzymes, to form endosomes.5 Within the endo- between peptides derived from their own (self) pro- somes, the ingested proteins are degraded, first to teins and those derived from foreign (nonself) pro- peptides and then, in some vesicles, into amino acids teins. Jawed vertebrates, by contrast, use the peptides for reuse. derived from foreign (usually microbial) proteins to This mode of protein processing must have evolved mark infected cells for destruction. at an early stage in the history of living forms. Later, In an uninfected cell, “housekeeping” proteasomes the jawed vertebrates found a new use for it by en- continuously churn out self peptides, some of which listing it in the defense of the body against patho- are picked up by molecules called “transporters asso- gens. Normally, the proteins that undergo recycling ciated with antigen processing,” or TAPs, encoded by are the organism’s own, but in infected cells, proteins the TAP1 and TAP2 genes.5 The TAP1 and TAP2 Volume 343 Number 10 · 703 The New England Journal of Medicine Downloaded from nejm.org at UC SHARED JOURNAL COLLECTION on May 26, 2011. For personal use only. No other uses without permission. Copyright © 2000 Massachusetts Medical Society. All rights reserved. The New England Journal of Medicine way to the luminal surface of the endoplasmic retic- Class I Class II ulum. There, the emerging chains are attended by a Peptide-binding? suite of molecular chaperones — calnexin, calreticu- groove lin, endoplasmic reticulum p57, TAP-binding pro- tein (also referred to as tapasin), and perhaps others a2 a1 — which ensure that the polypeptides do not fold a1 b1 prematurely, that they are properly glycosylated, that the a chain meets beta2-microglobulin at the appro- priate time, and that when this moment comes, the union proceeds without a hitch. A class I molecule a b a b a3 b2m 2 2 is then pinioned by the TAP-binding protein to the TAP molecule for loading. When a suitable peptide emerges from the TAP channel, the peptide-binding groove (Fig. 2) of the waiting class I molecule snags TM TM TM it. The loaded molecule then undocks from the com- plex of TAP-binding protein and TAP and sets off Plasma? on a journey to the surface of the cell. There, the membrane class I molecule remains anchored in the plasma mem- Cytoplasmic? Cytoplasmic? brane by the transmembrane region of the a chain. tail tail In this position, it displays the bulk of the a chain (the a1, a2, and a3 domains shown in Fig. 2), the peptide, and the associated beta2-microglobulin to Figure 2. Structure of HLA Class I and Class II Molecules.
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