Human Leukocyte Antigen Homozygosity Research Articles

HLA homozygosity is associated with Non-Hodgkin lymphoma

The “heterozygote advantage” hypothesis has been postulated regarding the role of human leukocyte antigen (HLA) in non-Hodgkin lymphoma (NHL), where homozygous loci are associated with an increased risk of disease. In this retrospective study, we analyzed the HLA homozygosity of 3789 patients with aplastic anemia (AA), acute lymphocytic leukemia (ALL), acute myeloblastic leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), myelodysplastic syndrome (MDS), multiple myeloma (MM), and non-Hodgkin lymphoma (NHL) at HLA-A, B, C, DRB1 and DQB1 loci compared to 169,964 normal controls. HLA homozygosity at one or more loci was only associated with an increased risk in NHL patients (OR = 1.28, 95% CI [1.09, 1.50], p = 0.002). This association was not seen in any of the other hematologic diseases. Homozygosity at HLA-A alone, HLA-B + C only, and HLA-DRB1 + DQB1 only was also significantly associated with NHL. Finally, we observed a 17% increased risk of NHL with each additional homozygous locus (OR per locus = 1.17, 95% CI [1.08, 1.25], p trend = 2.4 × 10−5). These results suggest that reduction of HLA diversity could predispose individuals to an increased risk of developing NHL.

Abstract 5132: HLA-I homozygosity as a protective biomarker for developing immune related adverse events (irAE) among non-small cell lung cancer (NSCLC) patients treated with single agent immunotherapy in the first- or second-line setting

Abstract Background: Biomarkers that predict risk of immune-mediated adverse events (irAEs) among non-small cell lung cancer (NSCLC) patients may reduce morbidity and mortality associated with these treatments. While it has been suggested that human leukocyte antigen (HLA-I) homozygosity is associated with short survival among these patients, its association with toxicity has not been examined. Method: We carried out high resolution HLA typing on 193 NSCLC patients treated with anti-PD1/PDL1. Toxicity data was collected and graded as per common terminology criteria for adverse event (CTCAE) v5.0. We investigated the correlation between HLA-I/II homozygosity, different supertypes and alleles with irAE. In addition, we investigated the relationship between irAE, clinical benefit rate (CBR), progression free survival (PFS) and overall survival (OS). Results: We recorded 103 irAE among 179 (58%) patients suitable for analysis. Homozygosity at one or more HLA-I loci, but not HLA-II was associated with increased risk of irAE with relative risk RR=0.57 (95%CI 0.31-0.96, P=0.025). None of the patients with homozygosity at one or more HLA-I loci developed pneumonitis of any grade (P=0.037) or grade 3 toxicity (P=0.023). The presence of HLA-A03 (N=49) supertype or HLA-DRB1*0401 (N=22) genotype was correlated with increased risk of developing irAE, (RR=1.40, 95%CI 0.99-2.01, P=0.039) and (RR=1.51, 95%CI 1.05-2.06, P=0.023) respectively. In contrast, none of the patients with HLA-DQB1*0301 (N=5) experienced gastrointestinal toxicity (P=0.048) and HLA-DRB1*15:01 (N=16) seems to be protective against developing arthralgia (RR=0.19, 95%CI 0.03-1.0, P=0.041). The occurrence of any irAE was associated with improved ORR, PFS and OS (RR=1.94, 95%CI 1.57-2.47, P less than 0.0001), (HR=0.37, 95%CI 0.25-0.54, P less than 0.0001) and (HR=0.26, 95%CI 0.16-0.41, P less than 0.0001) respectively. The usage of steroid to treat irAE did not diminish the positive clinical outcome. Conclusions: Homozygosity at one or more HLA-I loci can be a useful biomarker to predict irAE among NSCLC patients treated with anti-PD1/PD-L1 in the first- or second-line setting. This is more important among patients who developed pneumonitis or Grade 3 toxicities. However, the occurrence of any irAE is correlated with favourable clinical outcome. Citation Format: Afaf Abed, Ngie Law, Leslie Calapre, Johnny Lo, Vikas Bhat, Samantha Bowyer, Michael Millward, Elin Gray. HLA-I homozygosity as a protective biomarker for developing immune related adverse events (irAE) among non-small cell lung cancer (NSCLC) patients treated with single agent immunotherapy in the first- or second-line setting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5132.

9P HLA-I homozygosity as a predictive biomarker for developing immune related adverse events (irAE) among non-small cell lung cancer (NSCLC) patients treated with single agent immunotherapy

Immune checkpoint inhibitors have revolutionised the management of NSCLC. However, the development of irAEs is associated with morbidity that can be lifelong and even fatal. While it has been suggested that human leukocyte antigen (HLA-I) homozygosity is associated with worse overall survival among NSCLC treated with single agent immunotherapy, its association with toxicity has not been examined.

Patient human leukocyte antigen (HLA) genotype may predict response to anti-programmed death receptor 1 (anti-PD1) in advanced melanoma.

e21512 Background: Anti-PD-1 therapy has improved the outcome of advanced melanoma patients with a 5-year survival rate of about 40-45%. However, biomarkers predictive of response to immune checkpoint blockade therapy are lacking. There is limited data on the utility of host germline human leucocyte antigen (HLA) genotype as a predictor of response to anti-PD-1 therapy in advanced melanoma. Here, we investigate the prognostic value of HLA in predicting survival outcomes of patients with unresectable locally advanced, metastatic melanoma on anti-PD-1 therapy. Methods: Blood was collected from 113 metastatic melanoma patients who were treated with anti-PD-1 therapy at two major oncology centres in Western Australia. High quality DNA was extracted from white blood cells and subsequently HLA-I and HLA-II typed using clinically validated assay. Univariate analyses were conducted using Cox regression model correlating homozygosity at HLA-I and HLA-II loci with overall survival (OS). HLA-A and HLA-B were classified into 12 supertypes and correlated with OS. Multivariate analyses were performed while controlling for age, gender, prior therapy, BRAF mutation status, ECOG performance status and presence of liver and brain metastases. Results: Homozygosity at HLA-I or HLA-II loci was not associated with OS. However, the absence of HLA-B62 supertype was associated with a trend towards improved OS (HR: 0.53 [95% CI:0.25-1.10]; P = 0.09) as reported previously. Notably, the absence of HLA-B27 supertype was associated with improved OS which was statistically significant (HR: 0.45 [95% CI:0.24-0.85]; P = 0.01). In multivariate analyses, the prognostic value of HLA-B27 supertype (HR: 0.38 [95% CI:0.19-0.76]; P = 0.006) was maintained, whereas the prognostic value of HLA-B62 supertype significantly improved (HR: 0.42 [95% CI:0.19-0.94]; P = 0.03). Conclusions: Our results suggest a limited role of HLA homozygosity in predicting survival of melanoma patients treated with anti-PD-1 therapy. However, we identified that the absence of HLA-B62 and HLA-B27 supertype is associated with improved survival benefit. Therefore, HLA-B27 and HLA-B62 supertype may be used as adjunct biomarkers of response to anti-PD-1 therapy in patients with melanoma in addition to PD-L1 status, pending validation in prospective randomised clinical trials.

Prognostic value of HLA-I homozygosity in patients with non-small cell lung cancer treated with single agent immunotherapy

BackgroundWe aimed to assess the impact of genomic human leukocyte antigen (HLA)-I/II homozygosity on the survival benefit of patients with unresectable locally advanced, metastatic non-small lung cancer treated by single-agent...

Abstract 6684: Association of human leukocyte antigen (HLA) homozygosity with unfavorable clinical outcomes in patients with non-small cell lung cancer (NSCLC) treated with PD-L1 inhibitors as frontline therapy

Abstract Background: High polymorphic diversity in HLA class I (HLA-I) is essential for successful immunologic control of cancer. Lung cancer patients with maximal HLA-I heterozygosity treated with single-agent PD-L1 inhibitors as their second-line or beyond were reported with longer overall survival. However, the role of HLA heterozygosity for patients with NSCLC who received single-agent immunotherapy with or without chemotherapy as their first-line has not been reported. Methods: Patients with unresectable stage III or IV NSCLC who underwent next-generation sequencing with HLA typing were enrolled in our study (N=27). HLA genotypes were determined using DNA sequencing data. They received either pembrolizumab (N=5) or pembrolizumab plus chemotherapy (N=22) as their first-line treatment. Kaplan-Meier curves were constructed to compare survival outcomes according to HLA (homozygous vs. heterozygous) and tumor mutation burden (TMB, above vs. below median) status. A log-rank test was applied to compare Kaplan-Meier curves between groups. Hazard ratios were derived from the Cox-proportional hazards model with adjustment for baseline characteristics including age, sex, and TMB. Results: We determined HLA-I genotypes consisting of two alleles in 27 patients with NSCLC. Among these enrollees, 23 patients (85.2%) were heterozygous at every HLA-I locus and four patients (14.8%) were homozygous at more than one HLA-I locus. Response Evaluation Criteria in Solid Tumors (RECIST) evaluable patients were 19. In the HLA-heterozygous group (N=15), three patients (20%) had partial response (PR), eight patients (53.3%) had stable disease, and four patients (26.7%) had progressive disease (PD), whereas in the HLA-homozygous group (N=4), one (25%) had PR, one (25%) had SD, and two (50%) had PD. The disease control rates (CR, PR, and SD) were 73.3% in the HLA-heterozygous group and 50% in the HLA-homozygous group. Homozygosity at HLA-I genes seemed to be associated with shorter progression-free survival (PFS, HR=3.2, 95% CI=0.71-15, p=0.13) compared with heterozygosity at HLA-I genes. The HLA-heterozygous group had longer median PFS than the HLA-homozygous group (19 vs. 9.5 months, Log-rank p=0.11). When we controlled the effect of HLA homozygosity on PFS for age, sex, and TMB, the adjusted HRs were 4.4[0.82-23], 3.1[0.69-14] and 1.9[0.36-9.8] respectively. Conclusion: No data exists on the effect of HLA homozygosity on clinical outcomes of patients treated with immunotherapy with or without chemotherapy as frontline treatment. We for the first time report that in such setting HLA homozygosity may be associated with worse outcomes. Citation Format: Dongyup Lee, Jonghanne Park, Horyun Choi, Gahyun Gim, Sukjoo Cho, Leeseul Kim, Cyra Y. Kang, Pedro Viveiros, Young Kwang Chae. Association of human leukocyte antigen (HLA) homozygosity with unfavorable clinical outcomes in patients with non-small cell lung cancer (NSCLC) treated with PD-L1 inhibitors as frontline therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6684.

Conflicting HLA assignment by three different typing methods due to the apparent loss of heterozygosity in the MHC region.

Loss of heterozygosity (LOH) has been reported to cause false human leukocyte antigen (HLA) homozygous typing results in pre-transplant patients suffering from haematological malignancies, who in fact are HLA heterozygous. This poses a challenge for histocompatibility testing, as a stem cell graft from a genuinely HLA homozygous donor to a mistyped patient may lead to acute life-threatening graft-vs-host disease. LOH in the HLA region on chromosome 6 is known to be quite common in solid tumours, helping malignant cells to escape T-cell surveillance, but the incidence in haematological malignancies is less well known and the estimates vary. Here we report LOH in the HLA region of five patients with haematological malignancy. We found considerable differences in sensitivity between the three different HLA typing methods used in our laboratory: SSP was clearly the most sensitive method for detecting the lost haplotype, followed by rSSO, while SBT was the least sensitive technique. A subsequent, retrospective genotyping of 65 HLA homozygous haematological patients by SSP method showed no mistyped LOH cases in our laboratory in the past 10 years. The frequency of HLA homozygosity was found to be similar between haematological patients and control groups. It is important for an HLA laboratory to be aware of the differences in various HLA typing techniques' sensitivity for detecting an under-represented haplotype between HLA typing techniques when genotyping patients with haematological diseases. It is advisable for HLA laboratories to have at least two different methods with different sensitivities in their repertoire to be able to retype samples when a false homozygous result is suspected.

Associations of HLA Class I antigen specificities and haplotypes with disease progression in HIV-1-infected Hans in Northern China

The human leukocyte antigen (HLA) allele frequencies, which differ among various ethnic populations, may result in population-specific effects on HIV-1 disease progression. No large-scale study has yet been conducted on the Chinese population. In this study, HLA class I antigen specificities were determined in a cohort including 105 long-term non-progressors (LTNPs) and 321 typical progressors (TPs), who were recruited from HIV-1-infected Northern Han Chinese, to determine the associations between certain HLA types and HIV-1 disease progression. The frequencies of HLA class I specificities and haplotypes among the two groups were compared using binary logistic stepwise regression. Results showed that HLA-A∗30-B∗13-C∗06 (OR=0.387, P=0.019) and B∗67 (OR=0.134, P=0.005) were associated with a long-term non-progressing condition, and C∗01 (OR=2.539, P=0.050) was overrepresented in TPs after adjusting for non-genetic factors (sex, age, the location of patients, HIV subtype and the route of infection). The influence of HLA homozygosity on HIV disease progression was also analyzed. However, homozygosity at HLA-A, HLA-B or HLA-C conferred no observable disadvantage in our study population (P=0.730, 0.246 and 0.445, respectively). These findings suggest that the host’s genetics make important contributions to HIV viral control and may help to develop peptide-based vaccines for this population.

Human leukocyte antigens and cellular immune responses to anthrax vaccine adsorbed.

Interindividual variations in vaccine-induced immune responses are in part due to host genetic polymorphisms in the human leukocyte antigen (HLA) and other gene families. This study examined associations between HLA genotypes, haplotypes, and homozygosity and protective antigen (PA)-specific cellular immune responses in healthy subjects following immunization with Anthrax Vaccine Adsorbed (AVA). While limited associations were observed between individual HLA alleles or haplotypes and variable lymphocyte proliferative (LP) responses to AVA, analyses of homozygosity supported the hypothesis of a "heterozygote advantage." Individuals who were homozygous for any HLA locus demonstrated significantly lower PA-specific LP than subjects who were heterozygous at all eight loci (median stimulation indices [SI], 1.84 versus 2.95, P = 0.009). Similarly, we found that class I (HLA-A) and class II (HLA-DQA1 and HLA-DQB1) homozygosity was significantly associated with an overall decrease in LP compared with heterozygosity at those three loci. Specifically, individuals who were homozygous at these loci had significantly lower PA-specific LP than subjects heterozygous for HLA-A (median SI, 1.48 versus 2.13, P = 0.005), HLA-DQA1 (median SI, 1.75 versus 2.11, P = 0.007), and HLA-DQB1 (median SI, 1.48 versus 2.13, P = 0.002) loci, respectively. Finally, homozygosity at an increasing number (≥ 4) of HLA loci was significantly correlated with a reduction in LP response (P < 0.001) in a dose-dependent manner. Additional studies are needed to reproduce these findings and determine whether HLA-heterozygous individuals generate stronger cellular immune response to other virulence factors (Bacillus anthracis LF and EF) than HLA-homozygous subjects.

Dizygotic twins discordant for HIV-1 despite vertical transmission prophylaxis: was human leukocyte antigen homozygosity of disadvantage to the infected twin?

Dizygotic twins discordant for HIV-1 despite vertical transmission prophylaxis: was human leukocyte antigen homozygosity of disadvantage to the infected twin?

Impact of the 1998 UK National Allocation Scheme for Deceased Heartbeating Donor Kidneys

National and regional strategies for allocating deceased heartbeating (DHB) donor kidneys to patients awaiting transplant are of great importance and have major implications for patients and healthcare systems. We describe the rationale for the 1998 National Kidney Allocation Scheme (1998 NKAS) and its impact on renal transplantation in the United Kingdom over 5 years. The 1998 NKAS was based on three tiers of patients defined by human leukocyte antigen (HLA) mismatch. This involved national allocation of well-matched kidneys in tiers 1 and 2, with regional allocation for less well-matched patients in tier 3. Pediatric patients (younger than 18 years) and regional patients were prioritized in tiers 1 and 2, with a points score based on six factors determining the specific priority order for allocation. The 1998 NKAS allocated approximately half the kidneys from DHB donors to the national transplant list and resulted in significantly improved HLA matching, more than doubling the proportion of transplants that were 000 HLA-A, -B, and -DR mismatched from 7% to 16% for adults. Pediatric patients achieved comparable levels of HLA matching to adult patients for the first time in the United Kingdom through improved access to adult donor organs. The scheme also benefited highly sensitized patients and improved equity with regard to patient blood group, rareness of HLA type, and HLA homozygosity. The 1998 NKAS represented a significant advance for the allocation of DHB donor kidneys in the United Kingdom and, while not addressing inequities in access to transplant, it did largely achieve the principal goal of improving HLA matching.

Acute Graft-Versus-Host-Disease in Kidney Transplantation: Case Report and Review of Literature

Graft-versus-host-disease (GVHD) is a complication of solid organ transplantation, most commonly of the small bowel or liver. Herein, we have presented a case of GVHD in a 27-year-old man who underwent an human leukocyte antigen (HLA) minor mismatch renal transplantation from his father. After the procedure, the patient presented with a fever, skin rash, and watery diarrhea. An allograft kidney biopsy demonstrated no sign of rejection; however, anti-A antibody was detected in plasma and progressive anemia was attributed to hemolytic anemia owing to a passenger lymphocyte syndrome. From those findings, we suspected that the clinical symptoms were caused by acute GVHD. An endoscopic biopsy of the colon revealed apoptotic cells consistent with the disease. We found reports of only 5 other GVHD cases after kidney transplantation. Several risk factors are associated with GVHD, such as transfer of graft lymphocytes, donor HLA homozygosity, and a relationship between recipient immunogenicity and immunosuppression. In this case, detection led to early diagnosis of donor-derived GVHD due to passenger lymphocyte syndrome. It is important keep GVHD in mind and to understand its risk factors as the mortality rate is high.

Maternal HLA Homozygosity and Mother‐Child HLA Concordance Increase the Risk of Vertical Transmission of HIV‐1

Mother-child human leukocyte antigen (HLA) concordance and maternal HLA homozygosity may increase the risk of vertical transmission of human immunodeficiency virus type 1 (HIV-1) risk by reducing infant immune responses. We analyzed mother-child HLA concordance and maternal HLA homozygosity in a Kenyan perinatal cohort receiving antenatal zidovudine. HLA concordance was scored as the number of shared class I alleles, and relative risk estimates were adjusted for maternal HIV-1 load. Among 277 mother-infant pairs, HIV-1 transmission occurred in 58 infants (21%), with in utero transmission in 21 (36%), peripartum transmission in 26 (45%), and transmission via breast-feeding in 11 (19%). With increased concordance, we observed a significant increase in the risk of transmission overall (adjusted hazard ratio [aHR], 1.3 [95% confidence interval {CI}, 1.0-1.7]; P = .04 in utero (adjusted odds ratio, 1.72 [95% CI, 1.0-1.7]; P = .04), and via breast-feeding (aHR, 1.6 [95% CI, 1.0-2.5]; P = .04). Women with homozygosity had higher plasma HIV-1 RNA levels at 32 weeks of gestation (5.1 vs. 4.8 log(10) copies/mL; P = .03) and an increased risk of transmission overall (aHR, 1.7 [95% CI, 1.1-2.7]; P = .03) and via breast-feeding (aHR, 5.8 [95% CI, 1.9-17.7]; P = .002). The risks of overall, in utero, and breast milk HIV-1 transmission increased with HLA concordance and homozygosity. The increased risk may be due to reduced alloimmunity or less diverse protective immune responses.

Genetic insights into the disease mechanisms of type II mixed cryoglobulinemia induced by hepatitis C virus

The ability of the immune system to distinguish between self and non-self is critical to the functioning of the immune response. A breakdown in these mechanisms can lead to the onset of autoimmune disease. Clinical and molecular data suggest that shared immunogenetic mechanisms lead to the autoimmune process. The most studied part of the autoimmune process is the human leukocyte antigen (HLA) region. Recently, progress has been made in narrowing down HLA cluster classifications based on structural and functional features of HLA alleles. Using this approach we have investigated 175 patients with hepatitis C virus (HCV)-induced type II cryoglobulinemia (MC), and compared them to a control group of 14,923 bone marrow donors. Additionally, we investigated the frequency of HLA homozygosity in the same groups of subjects. Our results provide evidence of a role for DR5 and DQ3 HLA class II clusters and a higher frequency of HLA homozygous leading to the clinical outcome of type II mixed cryoglobulinemic autoimmune disease. The DR5 cluster is characterized by a Glu in β9 and its polymorphism is connected with preferred anchors at β9 of the binding peptide, while the DQ3 cluster is characterized by Glu B86 and Leu B87, which allows the binding of large hydrophobic amino acids at p1 of the binding peptide. The mechanisms by which variations in HLA lead to autoimmunity remain unknown, although they are likely to be mediated by continuous presentation of HCV epitopes to T cells and a genetic background that limits the effective clearance of HCV. The results presented in this paper have increased our knowledge of the mechanism of autoimmune disease and B-cell lymphoproliferation during HCV infection. The work was performed in accordance with the principles of the 1983 Declaration of Helsinki. There is no conflict of interest.

Extinction of the Human Leukocyte Antigen Homozygosity Effect After Two Doses of the Measles-Mumps-Rubella Vaccine

We have reported associations between human leukocyte antigen (HLA) homozygosity and low measles antibody levels after one dose of the measles, mumps, and rubella (MMR) vaccine. Here, we examined associations between HLA homozygosity and immune responses to MMR after two doses of vaccine. We examined associations between HLA homozygosity and measles antibody levels in a group of 178 children (cohort 1) as well as associations between homozygosity and antibody levels and lymphoproliferative responses to MMR in 346 children (cohort 2). In cohort 1, HLA homozygotes and heterozygotes had similar increases in measles antibody levels after a second dose of measles vaccine. In cohort 2, HLA homozygosity was not associated with measles immune measures after two doses of vaccine. Homozygosity at the DPB locus was associated with increased rubella antibody levels, and homozygosity at the class IA alleles was associated with lower mumps lymphoproliferative response. Homozygosity at increasing numbers of loci was also associated with lower mumps antibody levels and lymphoproliferative response. Therefore, two doses of the MMR vaccine appear to induce sufficient antibody levels and lymphoproliferative responses against measles and rubella, regardless of HLA homozygosity status. However, children who are HLA homozygous may be less protected against mumps compared with children who are heterozygous.

High frequency of homozygosity of the HLA region in melanoma cell lines reveals a pattern compatible with extensive loss of heterozygosity.

Malignant transformation of cells is frequently associated with abnormalities in human leukocyte antigen (HLA) expression. MHC class I loss or down-regulation in cancer cells is a major immune escape route used by a large variety of human tumours to evade antitumour immune responses mediated by cytotoxic T lymphocytes. The goal of our study was to explore HLA genotyping and phenotyping in a variety of melanoma tumour cell lines. A total of 91 melanoma cell lines were characterised for HLA class I and II genotype. In addition, 61 out of the 91 cell lines were also analysed for HLA class I and II cell surface molecule expression by flow cytometry. Unexpectedly, we found that 19.7% of the melanoma cell lines were homozygous for HLA class I genotypes, sometimes associated with HLA class II homozygosity (8.79%) and sometimes not (10.98%). The frequency of homozygosity was significantly higher compared with the control groups (1.6%). To identify the reasons underlying the high frequency of HLA homozygosity we searched for genomic deletions using eight pairs of highly polymorphic microsatellite markers covering the entire extended HLA complex on the short arm of chromosome 6. Our results were compatible with hemizygous deletions and suggest that loss of heterozygosity on chromosome arm 6p is a common feature in melanoma cell lines. In fact, although autologous normal DNA from the patients was not available and could not be tested, the retention in some cases of heterozygosity for a number of microsatellite markers would indicate a hemizygous deletion. In the rest of the cases, markers at 6p and 6q showed a single allele pattern indicating the probable loss of part or the whole of chromosome 6. These results led us to conclude that loss of heterozygosity in chromosome 6 is nonrandom and is possibly an immunologically relevant event in human malignant melanoma. Other well-established altered HLA class I phenotypes were also detected by flow cytometry that correspond to HLA class I total loss and HLA-ABC and/or specific HLA-B locus down-regulation.

Associations between human leukocyte antigen homozygosity and antibody levels to measles vaccine.

The association between human leukocyte antigen (HLA) homozygosity and measles antibody levels was assessed in a volunteer group of 242 children. Serum samples were tested for measles IgG antibodies, class I and class II HLA alleles were typed, and associations were examined between HLA homozygosity and antibody levels. Children who were homozygous for at least 1 locus were twice as likely to be seronegative (odds ratio, 1.97; 95% confidence interval, 1.08-3.61). Children who were homozygous at >/=1 loci were increasingly likely to be seronegative (chi(2) test for trend; P=.02). When serum antibody levels were examined as continuous variables, children who were homozygous at certain loci tended to have lower mean antibody levels. These results suggest that lack of HLA diversity may limit the range of peptides that can be presented to antibody-producing cells, potentially resulting in a decreased immune response to viral infections.

Major histocompatibility complex, t-complex, and leukemia.

In experimental models, leukemia was the first disease shown to have an association with the major histocompatibility complex (MHC) genes. In humans, several allelic human-leukocyte antigen (HLA) associations also have been recognized. In addition to allelic associations, atypical HLA segregation patterns have been observed in leukemic families. These include a higher frequency of HLA-identical unaffected siblings, increased HLA homozygosity and increased maternal HLA-DR identity. These observations suggest preferential transmission of disease-associated haplotypes and a male transmission bias in leukemic families. The lack of disease-specific segregation, however, supports the idea that the HLA system is not directly relevant in leukemogenesis. Therefore, the existence of another genetic region linked to the MHC, causing segregation distortion, and containing recessive leukemia susceptibility genes may be postulated. The mouse t-complex would fit this model. This gene complex has recessive (semi-) lethal genes, is transmitted preferentially through fathers, and both the mouse t-complex and its rat homolog, growth and reproduction complex grc, confer susceptibility to carcinogenesis. This model could also explain the increased spontaneous abortion rate in mothers of leukemic patients, epidemiologic associations of leukemia with oral clefts and neuroectodermal tumors, and the transmission of a radiation-induced leukemia risk through fathers. Such segregation distortion might be the reason behind the maintenance of a gene(s) with a lethal effect in the population.