An Ancient, MHC-Linked, Nonclassical Class I Lineage in Cartilaginous Fish.

Cartilaginous fishes, or chondrichthyans, are the oldest jawed vertebrates that have an adaptive immune system based on the MHC and Ig superfamily-based AgR. In this basal group of jawed vertebrates, we identified a third nonclassical MHC class I lineage (UDA), which is present in all species analyzed within the two major cartilaginous subclasses, Holocephali (chimaeras) and Elasmobranchii (sharks, skates, and rays). The deduced amino acid sequences of UDA have eight out of nine typically invariant residues that bind to the N and C termini of bound peptide found in most vertebrae classical class I (UAA); additionally, the other predicted 28 peptide-binding residues are perfectly conserved in all elasmobranch UDA sequences. UDA is distinct from UAA in its differential tissue distribution and its lower expression levels and is mono- or oligomorphic unlike the highly polymorphic UAA UDA has a low copy number in elasmobranchs but is multicopy in the holocephalan spotted ratfish (Hydrolagus colliei). Using a nurse shark (Ginglymostoma cirratum) family, we found that UDA is MHC linked but separable by recombination from the tightly linked cluster of UAA, TAP, and LMP genes, the so-called class I region found in most nonmammalian vertebrates. UDA has predicted structural features that are similar to certain nonclassical class I genes in other vertebrates, and, unlike polymorpic classical class I, we anticipate that it may bind to a conserved set of specialized peptides.

COVID-19 Pandemic: Escape of Pathogenic Variants and MHC Evolution.

We propose a new hypothesis that explains the maintenance and evolution of MHC polymorphism. It is based on two phenomena: the constitution of the repertoire of naive T lymphocytes and the evolution of the pathogen and its impact on the immune memory of T lymphocytes. Concerning the latter, pathogen evolution will have a different impact on reinfection depending on the MHC allomorph. If a mutation occurs in a given region, in the case of MHC allotypes, which do not recognize the peptide in this region, the mutation will have no impact on the memory repertoire. In the case where the MHC allomorph binds to the ancestral peptides and not to the mutated peptide, that individual will have a higher chance of being reinfected. This difference in fitness will lead to a variation of the allele frequency in the next generation. Data from the SARS-CoV-2 pandemic already support a significant part of this hypothesis and following up on these data may enable it to be confirmed. This hypothesis could explain why some individuals after vaccination respond less well than others to variants and leads to predict the probability of reinfection after a first infection depending upon the variant and the HLA allomorph.

Mechanisms of HLA-DP Antigen Processing and Presentation Revisited.

Polymorphisms in HLA-DP can modulate interactions with the invariant chain chaperone, contributing independently to differences in the peptide repertoire presented on DP. The resulting presentation of intracellular antigens directly to CD4+ T cells may partly explain genetic and clinical studies describing previously unexplained links between polymorphism in DP and disease.

Granzyme B levels and granzyme B polymorphisms in peripheral blood of patients with endometriosis: a preliminary study.

The chronic course of endometriosis suggests that the immune system may play a role in its aetiology. There may be resistance to cell lysis, as well as an immune defect underlying endometriosis. Granzyme B is a serine protease that is secreted by Natural Killer (NK) cells and cytotoxic T lymphocytes during a cellular immune response and can induce apoptosis. The aim of this study was to evaluate the relationship between both Granzyme B levels and Granzyme B gene polymorphisms in endometriosis patients. Women between the ages of 20 - 45 were included in the study. The patients were divided into two groups: those diagnosed with endometriosis and those who had not been diagnosed with endometriosis. In the blood samples, Granzyme B gene polymorphisms and serum levels of Granzyme B were studied. There was no difference between the groups in terms of median Granzyme B levels and the presence of AA, AG, and GG genotypes. There was a difference in median granzyme levels for the control group; the GG genotype was found at a lower frequency. The immune defect within endometriosis-related immune cells may not be exclusively due to Granzyme B. Other mediators that are secreted from immune cells may have additive effects.IMPACT STATEMENTWhat is already known on this subject? NK cells are cytotoxic and inhibit the implantation of autologous endometrial cells that are spilled into the peritoneum by retrograde menstruation. Thus, a reduction in NK cell activity may facilitate the progression of endometriosis. The literature review reveals that there are studies suggesting that NK cell activity may be insufficient in endometriosis. Granzyme B is a serine protease that is secreted by NK cells and cytotoxic T lymphocytes during a cellular immune response.What do the results of this study add? Granzyme B is one of the cytotoxic granules in NK and cytotoxic T lymphocyte cells and its genetic polymorphisms were tested in endometriosis. We found that median Granzyme B levels were significantly different in patients with the GG genotype in the control group, compared to those with the AA and AG genotype. However, this difference was not detected between the control and endometriosis groups.What are the implications of these findings for clinical practice and/or further research? Our results contribute to uncovering the pathogenesis of endometriosis since there are no previous studies in the literature regarding this topic. Although we did not find a difference, our results will inform further studies made on this topic. Studies with different molecules and an increased number of patients are needed. The immune defect of endometriosis may not be due exclusively to Granzyme B. Other mediators that are secreted from immune cells may have mutual effects and interactions.

Association between IL12B polymorphisms and inflammatory bowel disease in Caucasian population: A meta-analysis.

BACKGROUND: Published studies on association between IL12B (G/A) rs10045431, (T/C)rs6887695 polymorphisms and inflammatory bowel disease (IBD) risk in Caucasian population have yielded conflicting results. The aim of this study was to potentially provide more reliable conclusions by conducting a meta-analysis. METHODS: Published studies concerned association between IL12B rs10045431, rs6887695 polymorphisms and IBD were searched from the Wiley Online Library, PubMed, Web of Science and the CNKI database. The odds ratio (OR) with 95% confidence interval (CI) was calculated to evaluate the strength of the relationship. The false positive report probabilities (FPRPs) test and trial sequential analysis (TSA) was performed to investigated the reliability of results. RESULTS: A total of 20 studies comprising 10761 Crohn's disease (CD), 10921 ulcerative colitis (UC) and 18381 controls were included in this meta-analysis. Overall, the pooled results showed that IL12B rs6887695 polymorphism significantly increased both CD and UC risk under all model, while IL12B rs10045431 polymorphism dramatically decreased both CD and UC risk under all model. FPRP and TSA demonstrated that above associations was confirmed in the present study. CONCLUSION: The results of meta-analysis indicate IL12B rs10045431 and rs6887695 polymorphisms significantly associate with IBD in Caucasian population.

Association between HLA-A gene polymorphism and early-onset preeclampsia in Chinese pregnant women early-onset.

BACKGROUND: Preeclampsia is an idiopathic disease during pregnancy. This study explores the correlation between HLA-A polymorphism and the onset of preeclampsia. METHODS: The Illumina HiSeq2500 sequencing platform was used to genotyping HLA-A allele in venous blood DNA of 50 preeclampsia pregnant women and 48 normal pregnant women and umbilical cord blood DNA of their children of Han nationality in China. The frequencies and distributions of alleles and genotypes among the mothers and their children were compared between the two groups. The differences of frequencies and distributions of genotypes were compared between the two groups according to the mothers' genotype compatibility. RESULTS: Twenty HLA-A alleles were detected in preeclampsia pregnant women and normal pregnant women; 21 HLA-A alleles were found in preeclampsia group fetuses and 22 HLA-A alleles in control group fetuses. There was no statistical difference in the HLA-A genes' frequency between the two groups of pregnant women and their fetuses. When the sharing antigen was 1, the number of maternal-fetal pairs in the preeclampsia group was more than that in the control group; the difference was statistically significant (P < 0.05). The frequency of neither mother nor fetus carrying the HLA-A * 24: 02 gene in the preeclampsia group was significantly lower than that in the control group (P < 0.05). HLA-A gene homozygosity in fetuses of early-onset preeclampsia group was substantially higher than that of the control group (P = 0.0148); there is no significant difference in pregnant women's genes homozygosity between early-onset preeclampsia group and the control group. CONCLUSIONS: HLA-A * 24: 02 may be a susceptibility gene for early preeclampsia.

Migrants and allergy: a new view of the atopic march.

Summary: Atopy is the result of the influence of environmental factors on genetically predisposed individuals. Migration flows represent an interesting model to study the possible reciprocal roles of genes and environment. In this review the following issues influencing the development of allergic sensitization and/or atopic disorders in migrants will be rooted out: 1) ethnicity, genetic polymorphisms and risk of atopy; 2) double faceted effects of parasitic infestations; 3) biodiversity loss and industrial progress. Moreover, an extensive revision of the literature about the relationship between the migratory status and allergy development is provided.

Co-evolution with chicken class I genes.

The concept of co-evolution (or co-adaptation) has a long history, but application at molecular levels (e.g., 'supergenes' in genetics) is more recent, with a consensus definition still developing. One interesting example is the chicken major histocompatibility complex (MHC). In contrast to typical mammals that have many class I and class I-like genes, only two classical class I genes, two CD1 genes and some non-classical Rfp-Y genes are known in chicken, and all are found on the microchromosome that bears the MHC. Rarity of recombination between the closely linked and polymorphic genes encoding classical class I and TAPs allows co-evolution, leading to a single dominantly expressed class I molecule in each MHC haplotype, with strong functional consequences in terms of resistance to infectious pathogens. Chicken tapasin is highly polymorphic, but co-evolution with TAP and class I genes remains unclear. T-cell receptors, natural killer (NK) cell receptors, and CD8 co-receptor genes are found on non-MHC chromosomes, with some evidence for co-evolution of surface residues and number of genes along the avian and mammalian lineages. Over even longer periods, co-evolution has been invoked to explain how the adaptive immune system of jawed vertebrates arose from closely linked receptor, ligand, and antigen-processing genes in the primordial MHC.

Co-evolution of NK receptors and HLA ligands in humans is driven by reproduction.

Allogeneic individuals co-exist during pregnancy in eutherian mammals. Maternal and fetal cells intermingle at the site of placental attachment in the uterus, where the arteries are remodeled to supply the fetus with oxygen and nutrients. This access by placental cells to the maternal supply line determines the growth and birth weight of the baby and is subject to stabilizing selection. Invading placental trophoblast cells express human leukocyte antigen class I ligands (HLA-E, HLA-G, and HLA-C) for receptors on maternal uterine natural killer (NK) and myelomonocytic cells, CD94/NKG2, leukocyte immunoglobulin-like receptor (LILR), and killer immunoglobulin receptor (KIR). Of these, only the KIR/HLA-C system is highly polymorphic. Different combinations of maternal KIR and fetal HLA-C variants are correlated with low birth weight and pre-eclampsia or high birth weight and obstructed labor, the two extremes of the obstetric dilemma. This situation has arisen because of the evolution of bipedalism and subsequently, in the last million years, larger brains. At this point, the human system began to reach a balance between KIR A and KIR B haplotypes and C1 and C2 epitopes of HLA-C alleles that reflects a functional compromise between the competing demands of immunity and reproduction.

The Behçet's disease-associated variant of the aminopeptidase ERAP1 shapes a low-affinity HLA-B*51 peptidome by differential subpeptidome processing.

A low-activity variant of endoplasmic reticulum aminopeptidase 1 (ERAP1), Hap10, is associated with the autoinflammatory disorder Behçet's disease (BD) in epistasis with HLA-B*51, which is the main risk factor for this disorder. The role of Hap10 in BD pathogenesis is unknown. We sought to define the effects of Hap10 on the HLA-B*51 peptidome and to distinguish these effects from those due to HLA-B*51 polymorphisms unrelated to disease. The peptidome of the BD-associated HLA-B*51:08 subtype expressed in a Hap10-positive cell line was isolated, characterized by mass spectrometry, and compared with the HLA-B*51:01 peptidome from cells expressing more active ERAP1 allotypes. We additionally performed synthetic peptide digestions with recombinant ERAP1 variants and estimated peptide-binding affinity with standard algorithms. In the BD-associated ERAP1 context of B*51:08, longer peptides were generated; of the two major HLA-B*51 subpeptidomes with Pro-2 and Ala-2, the former one was significantly reduced, and the latter was increased and showed more ERAP1-susceptible N-terminal residues. These effects were readily explained by the low activity of Hap10 and the differential susceptibility of X-Pro and X-Ala bonds to ERAP1 trimming and together resulted in a significantly altered peptidome with lower affinity. The differences due to ERAP1 were clearly distinguished from those due to HLA-B*51 subtype polymorphism, which affected residue frequencies at internal positions of the peptide ligands. The alterations in the nature and affinity of HLA-B*51·peptide complexes probably affect T-cell and natural killer cell recognition, providing a sound basis for the joint association of ERAP1 and HLA-B*51 with BD.

The Nature of Selection on the Major Histocompatibility Complex.

Only natural selection can account for the extreme genetic diversity of genes of the major histocompatibility complex (MHC). Although the structure and function of classic MHC genes is well understood at the molecular and cellular levels, there is controversy about how MHC diversity is selectively maintained. The diversifying selection can be driven by pathogen interactions and inbreeding avoidance mechanisms. Pathogen-driven selection can maintain MHC polymorphism based on heterozygote advantage or frequency-dependent selection due to pathogen evasion of MHC-dependent immune recognition. Empirical evidence demonstrates that specific MHC haplotypes are resistant to certain infectious agents, while susceptible to others. These data are consistent with both heterozygote advantage and frequency-dependent models. Additional research is needed to discriminate between these mechanisms. Infectious agents can precipitate autoimmunity and can potentially contribute to MHC diversity through molecular mimicry and by favoring immunodominance. MHC-dependent abortion and mate choice, based on olfaction, can also maintain MHC diversity and probably functions both to avoid genome-wide inbreeding and produce MHC-heterozygous offspring with increased immune responsiveness. Although this diverse set of hypotheses are often treated as competing alternatives, we believe that they all fit into a coherent, internally consistent thesis. It is likely that at least in some species, all of these mechanisms operate, leading to the extreme diversification found in MHC genes.

HLA Class I Chromosomal Region, Genes, and Products: Facts and Questions.

Among the various areas of recent investigation in the field of human MHC class I antigens, the following have been selected for discussion in this review: (1) classical HLA class I genes: are they ubiquitously expressed?, what are the special features of their polymorphism?, are HLA-C molecules functional?, (2) non-classical HLA class I gene products: how restricted is their tissue distribution?, do they exhibit a little polymorphism?, what is their function, if any? (3) non-HLA genes recently detected in the HLA class I chromosomal region: are some of them involved in immunological function and development?, (4) other novel coding sequences present, or possibly present, in the region: the hemochromatosis gene, grc region and associated tumor suppressor genes, housekeeping genes, human equivalent of the murine H-2M region and Ped gene; (5) transcriptional regulation: are there cis-regulatory elements, including locus control region(s). located elsewhere than in the promoters? are CpG methylation, gene imprinting, chromatin structure, DNA rearrangement also implicated? what are the transcription factors involved and how do they interact with each other? is there HLA class I locus-, allele-, or isoform-specific regulation? is class I gene expression dysregulated in human tumors? The answers to these questions are crucial for the development of the future directions for research.

lnterleukin-1 Receptor Antagonist.

The interleukin-1 receptor antagonist (IL-lra) is unusual in that it is the only known naturally occurring, cytokine receptor antagonist with no apparent agonist function. Over the last 5 years, since the cloning of the IL-lra cDNA sequence, there has been intensive research on the genetics, regulation, and potential therapeutic value of this protein. The later discovery of a second form of IL-lra in 1991 has complicated the picture. Whereas the originally described IL-lra is predominantly glycosylated and secreted (sIL-lra), the alternative isoform is unglycosylated and intracellular (icIL-lra). Although the biological roles of the two forms are still open to question, IL-lra is likely to be of great importance in the pathogenesis of both acute and chronic inflammatory diseases. A large body of evidence for this conclusion has come from animal models of inflammatory disease that respond well to administration of exogenous IL-lra. A role for recombinant IL-lra in the management of human disease is still under investigation. The two forms of IL-lra are encoded by a single gene by alternative usage of two first exons. Expression of sIL-lra and icIl-lra is regulated by two promoters. In this review I explore the genetics of the gene encoding IL-lra (IL-1RN) and the mechanisms of IL-lra gene activation to produce sIL-lra and icIL-lra. Also, possible biological roles for these immunomodulators in health and disease are discussed.

MHC Class I Chain-Related Gene A (MICA) Donor-Recipient Mismatches and MICA-129 Polymorphism in Unrelated Donor Hematopoietic Cell Transplantations Has No Impact on Outcomes in Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, or Myelodysplastic Syndrome: A Center for International Blood and Marrow Transplant Research Study.

Single-center studies have previously reported associations of MHC Class I Chain-Related Gene A (MICA) polymorphisms and donor-recipient MICA mismatching with graft-versus-host disease (GVHD) after unrelated donor hematopoietic cell transplantation (HCT). In this study, we investigated the association of MICA polymorphism (MICA-129, MM versus MV versus VV) and MICA mismatches after HCT with 10/10 HLA-matched (n = 552) or 9/10 (n = 161) unrelated donors. Included were adult patients with a first unrelated bone marrow or peripheral blood HCT for acute lymphoblastic leukemia, acute myeloid leukemia, or myelodysplastic syndrome that were reported to the Center for International Blood and Marrow Transplant Research between 1999 and 2011. Our results showed that neither MICA mismatch nor MICA-129 polymorphism were associated with any transplantation outcome (P < .01), with the exception of a higher relapse in recipients of MICA-mismatched HLA 10/10 donors (hazard ratio [HR], 1.7; P = .003). There was a suggestion of association between MICA mismatches and a higher risk of acute GVHD grades II to IV (HR, 1.4; P = .013) There were no significant interactions between MICA mismatches and HLA matching (9/10 versus 10/10). In conclusion, the findings in this cohort did not confirm prior studies reporting that MICA polymorphism and MICA mismatches were associated with HCT outcomes.

HLA-DMA polymorphisms differentially affect MHC class II peptide loading.

During the adaptive immune response, MHCII proteins display antigenic peptides on the cell surface of APCs for CD4(+) T cell surveillance. HLA-DM, a nonclassical MHCII protein, acts as a peptide exchange catalyst for MHCII, editing the peptide repertoire. Although they map to the same gene locus, MHCII proteins exhibit a high degree of polymorphism, whereas only low variability has been observed for HLA-DM. As HLA-DM activity directly favors immunodominant peptide presentation, polymorphisms in HLA-DM (DMA or DMB chain) might well be a contributing risk factor for autoimmunity and immune disorders. Our systematic comparison of DMA*0103/DMB*0101 (DMA-G155A and DMA-R184H) with DMA*0101/DMB*0101 in terms of catalyzed peptide exchange and dissociation, as well as direct interaction with several HLA-DR/peptide complexes, reveals an attenuated catalytic activity of DMA*0103/DMB*0101. The G155A substitution dominates the catalytic behavior of DMA*0103/DMB*0101 by decreasing peptide release velocity. Preloaded peptide-MHCII complexes exhibit ∼2-fold increase in half-life in the presence of DMA*0103/DMB*0101 when compared with DMA*0101/DMB*0101. We show that this effect leads to a greater persistence of autoimmunity-related Ags in the presence of high-affinity competitor peptide. Our study therefore reveals that HLA-DM polymorphic residues have a considerable impact on HLA-DM catalytic activity.

Positional identification of RT1-B (HLA-DQ) as susceptibility locus for autoimmune arthritis.

Rheumatoid arthritis (RA) is associated with amino acid variants in multiple MHC molecules. The association to MHC class II (MHC-II) has been studied in several animal models of RA. In most cases these models depend on T cells restricted to a single immunodominant peptide of the immunizing Ag, which does not resemble the autoreactive T cells in RA. An exception is pristane-induced arthritis (PIA) in the rat where polyclonal T cells induce chronic arthritis after being primed against endogenous Ags. In this study, we used a mixed genetic and functional approach to show that RT1-Ba and RT1-Bb (RT1-B locus), the rat orthologs of HLA-DQA and HLA-DQB, determine the onset and severity of PIA. We isolated a 0.2-Mb interval within the MHC-II locus of three MHC-congenic strains, of which two were protected from severe PIA. Comparison of sequence and expression variation, as well as in vivo blocking of RT1-B and RT1-D (HLA-DR), showed that arthritis in these strains is regulated by coding polymorphisms in the RT1-B genes. Motif prediction based on MHC-II eluted peptides and structural homology modeling suggested that variants in the RT1-B P1 pocket, which likely affect the editing capacity by RT1-DM, are important for the development of PIA.

Understanding the obstacle of incompatibility at residue 156 within HLA-B*35 subtypes.

Defining permissive and non-permissive mismatches for transplantation is a demanding challenge. Single mismatches at amino acid (AA) position 156 of human leucocyte antigen (HLA) class I have been described to alter the peptide motif, repertoire, or mode of peptide loading through differential interaction with the peptide-loading complex. Hence, a single mismatch can tip the balance and trigger an immunological reaction. HLA-B*35 subtypes have been described to evade the loading complex, 156 mismatch distinguishing B*35:01 and B*35:08 changes the binding groove sufficiently to alter the sequence features of the selected peptide repertoire. To understand the functional influences of residue 156 in B*35 variants, we analyzed the peptide binding profiles of HLA-B*35:01(156Leu), B*35:08(156Arg) and B*35:62(156Trp). The glycoprotein tapasin represents a target for immune evasions and functions within the multimeric peptide-loading complex to stabilize empty class I molecules and promote acquisition of high-affinity peptides. All three B*35 subtypes showed a tapasin-independent mode of peptide acquisition. HLA-B*35-restricted peptides of low- and high-binding affinities were recovered in the presence and absence of tapasin and subsequently sequenced utilizing mass spectrometry. The peptides derived from B*35 variants differ substantially in their features dependent on their mode of recruitment; all peptides were preferentially anchored by Pro at p2 and Tyr, Phe, Leu, or Lys at pΩ. However, the Trp at residue 156 altered the p2 motif to an Ala and restricted the pΩ to a Trp. Our results highlight the importance of understanding the impact of key micropolymorphism and how a single AA mismatch orchestrates the neighboring AAs.

MICA*A4 protects against ulcerative colitis, whereas MICA*A5.1 is associated with abscess formation and age of onset.

Ulcerative colitis (UC) is one of the two major forms of inflammatory bowel disease, the aetiology of which remains unknown. Several studies have demonstrated the genetic basis of disease, identifying more than 130 susceptibility loci. The major histocompatibility complex class I chain-related gene A (MICA) is a useful candidate to be involved in UC pathogenesis, because it could be important in recognizing the integrity of the epithelial cell and its response to stress. The aim of this study was to analyse the relationship between polymorphisms in the transmembrane domain of MICA and susceptibility to develop UC. A total of 340 patients with UC and 636 healthy controls were genotyped for MICA transmembrane polymorphism using a polymerase chain reaction (PCR) combined with fluorescent technology. Different MICA alleles were determined depending on the PCR product size. The allele MICA*A4 was less frequent in patients than in controls (P = 0·003; OR = 0·643), and this protective role is higher when it forms haplotype with B*27 (P = 0·002; OR = 0·294). The haplotype HLA-B*52/MICA*A6 was also associated with UC [P = 0·001; odds ratio (OR) = 2·914]. No other alleles, genotypes or haplotypes were related with UC risk. Moreover, MICA*A5.1 is associated independently with abscesses (P = 0·002; OR = 3·096) and its frequency is lower in patients diagnosed between ages 17 and 40 years (P = 0·007; OR = 0·633), meaning an extreme age on onset. No association with location, extra-intestinal manifestations or need for surgery was found.

Polymorphism in the innate immune receptor SIRPα controls CD47 binding and autoimmunity in the nonobese diabetic mouse.

The signal regulatory protein (SIRP) locus encodes a family of paired receptors that mediate both activating and inhibitory signals and is associated with type 1 diabetes (T1D) risk. The NOD mouse model recapitulates multiple features of human T1D and enables mechanistic analysis of the impact of genetic variations on disease. In this study, we identify Sirpa encoding an inhibitory receptor on myeloid cells as a gene in the insulin-dependent diabetes locus 13.2 (Idd13.2) that drives islet inflammation and T1D. Compared to T1D-resistant strains, the NOD variant of SIRPα displayed greater binding to its ligand CD47, as well as enhanced T cell proliferation and diabetogenic potency. Myeloid cell-restricted expression of a Sirpa transgene accelerated disease in a dose-dependent manner and displayed genetic and functional interaction with the Idd5 locus to potentiate insulitis progression. Our study demonstrates that variations in both SIRPα sequence and expression level modulate T1D immunopathogenesis. Thus, we identify Sirpa as a T1D risk gene and provide insight into the complex mechanisms by which disease-associated variants act in concert to drive defined stages in disease progression.

Distinct assembly profiles of HLA-B molecules.

MHC class I polymorphisms are known to influence outcomes in a number of infectious diseases, cancers, and inflammatory diseases. Human MHC class I H chains are encoded by the HLA-A, HLA-B, and HLA-C genes. These genes are highly polymorphic, with the HLA-B locus being the most variable. Each HLA class I protein binds to a distinct set of peptide Ags, which are presented to CD8(+) T cells. HLA-disease associations have been shown in some cases to link to the peptide-binding characteristics of individual HLA class I molecules. In this study, we show that polymorphisms at the HLA-B locus profoundly influence the assembly characteristics of HLA-B molecules and the stabilities of their peptide-deficient forms. In particular, dependence on the assembly factor tapasin is highly variable, with frequent occurrence of strongly tapasin-dependent or independent allotypes. Several polymorphic HLA-B residues located near the C-terminal end of the peptide are key determinants of tapasin-independent assembly. In vitro refolded forms of tapasin-independent allotypes assemble more readily with peptides compared to tapasin-dependent allotypes that belong to the same supertype, and, during refolding, reduced aggregation of tapasin-independent allotypes is observed. Paradoxically, in HIV-infected individuals, greater tapasin-independent HLA-B assembly confers more rapid progression to death, consistent with previous findings that some HLA-B allotypes shown to be tapasin independent are associated with rapid progression to multiple AIDS outcomes. Together, these findings demonstrate significant variations in the assembly of HLA-B molecules and indicate influences of HLA-B-folding patterns upon infectious disease outcomes.