HLA polymorphisms in Saudi Arabs

The HLA-A, -B, -C, -DR, Bf and GLO phenotypes of 109 unrelated Saudi Arab males have been determined. HLA-A and -B antigen frequencies were compared with data reported for European Caucasoids and various Arab populations. Most similarities in antigen frequencies were seen between Saudi Arab and Iraqi populations. A high frequency of Bw50 was observed in Saudi Arabs. The frequencies of HLA-DR antigens in Saudi Arabs were compared to European Caucasoids. HLA-DR7 was at high frequency in Saudi Arabs. Linkage disequilibria between alleles of HLA loci was examined. Many instances of previously reported antigen associations were seen in Saudi Arabs, together with a number of associations which have not been described elsewhere. HLA-Cw6-Bw50-DR7-BfS0.7 is suggested as being a common haplotype in Saudi Arabs.     

HLA polymorphisms and evolution.

Polymorphisms within the human MHC are of interest to immunologists, for their functional significance, and to geneticists, as markers of populations. Here, Eleanor Riley and Olle Olerup describe how molecular analysis of the HLA complex is beginning to reveal the true extent of class II diversity, and demonstrate the use of this information to clarify the historical relationships between different human populations.     

HLA polymorphisms in a Shanghai Chinese population

The frequencies of the HLA-A, B, C, D, DR and MB antigens have been determined in a homogeneous Shanghai Chinese population. Comparisons with the HLA-A and -B frequencies in other subsets of the Chinese population revealed some marked differences. No comparisons were possible for the D, DR and MB antigens since there were no previous studies of the antigens in those loci. We suggest that studies of the Chinese population should be confined to clearly defined homogeneous subsets. In this manner, the confounding effect of population heterogeneity may be avoided, and it is this heterogeneity which calls for extensive surveys of the huge Chinese population.     

HLA region microsatellite polymorphisms in juvenile arthritis

Abstract: A number of microsatellite polymorphisms located in the MHC region of the human chromosome 6 have been analysed in a large group of patients with juvenile arthritis (JA) ( n =177) and in 157 controls. There have been no significant associations for the alleles of the microsatellite polymorphisms D6S -105, D6S -510, TNFA, TNFC, TNFD, TNFE, HSP. Allele frequencies and HLA associations were listed for the non-associated micro-satellite loci. The microsatellite locus DQ CAR, which is localized between DQA1 and DQB1, shows a significant positive association with JA for the allele DQ CAR 121 and a negative association for the allele DQ CAR 111. The allele DQ CAR 121 is strongly associated with DQA1*0501 and with DQB1*0301 both in the normal controls and in the patient population. This pair of DQA/DQB alleles corresponds to the DQ molecule DQ7 on the cell surface, which has been described to be strongly associated with JA. Investigations of the two and three-point haplotypes of DQ CAR with alleles of its neighboring loci have shown that the association with DQ CAR 121 is secondary to the association with DQ7 previously observed. Thus, using eight HLA linked microsatellite polymorphisms in the region from HLA-A to HLA-DQ, we have not found any evidence for further loci which might be involved in the coding for susceptibility for JA.     

Mapping HLA for single nucleotide polymorphisms

Knowledge of DNA sequence variation may help us understand how genetic variability gives rise to functional variability and, in so doing, revolutionize the development of strategies to combat and prevent disease. Single nucleotide polymorphisms (SNPs) are stable, inherited, biallelic, single base pair differences which are present in the human genome at a density of 1 to 10 per 1,000 nucleotides. It is anticipated that SNPs will account for much of the functional heterogeneity in gene expression and protein activity exhibited in the human population. Susceptibility to or protection from a number of diseases, particularly those of autoimmune etiology, has been associated with specific alleles of the human leukocyte antigen (HLA) complex. Interestingly, the precise molecular defects in the HLA genes are unknown and the notion that non-HLA genes, within the same chromosomal region, are involved remains a formal possibility. We have determined the nucleotide sequence of a contiguous 2.2 Mbp segment of chromosome six that includes all of the HLA class I region, and have identified over 10,000 SNPs therein. Because of the derivative knowledge of gene and SNP content and position, the scientific community is now uniquely poised to identify disease-contributory SNPs that lie within the MHC.     

HLA polymorphisms and T cells in rheumatoid arthritis

A dense infiltrate of activated T cells, macrophages, and B cells in the synovial membrane is the cardinal pathological feature of rheumatoid arthritis (RA). Frequently, tissue infiltrating cells acquire a morphological organization reminiscent of secondary lymphoid tissue. The composition of the inflammatory lesions, the production of autoantibodies, and the association of disease risk with genes related to the HLA-D region have all been cited as evidence for a critical role of T cells in disease pathogenesis. Investigations on the precise role of HLA genes in RA have confirmed the importance of this genetic risk factor and have identified a consensus sequence within the HLA-DRBI genes. The observation that HLA polymorphisms are mostly associated with disease progression and severity and that a gene dose effect for HLA-DR genes is operational has challenged the simple model that HLA molecules select and present an arthritogenic antigen. Studies analyzing the repertoire of tissue infiltrating T cells have not been able to identify a dominant and common disease relevant T cell. The infiltrate is diverse in terms of T cell receptor gene usage but consistently includes clonally expanded populations. Recent evidence indicates that RA patients carry expanded CD4 clonotypes which are characterized by deficient CD28 expression and autoreactivity. These autoreactive CD4 T cells are not restricted to the joint, raising the possibility that rheumatoid synovitis is a manifestation of a systemic autoimmune disease. Support for this model has come from studies in T cell receptor (TCR) transgenic animals which develop inflammation of the synovial membrane stimulated by a T cell response to ubiquitously expressed self-MHC molecules. Antigens driving the chronic persistent immune response in RA may not be restricted to the joint but rather may be widely distributed, providing an explanation for the difficulties in identifying arthritogenic antigens directly or indirectly through the selection of joint infiltrating T cells.     

HLA polymorphisms in Sindhi community in Mumbai,India

Indian population is an amalgamation of various ethnicities, cultural and linguistic diversities, primarily due to marriages within a community. HLA-A, B and DRB1 alleles and haplotype frequencies were investigated in the Sindhi and compared with Marathi, Gujarati and North Indian population from Mumbai. This work is a part of a larger effort aimed at analysis of the HLA profile of diverse Indian ethnics to establish an umbilical cord stem cell panel in India. HLA polymorphisms at the HLA-A, B and DRB1 loci were determined in 413 cord blood samples by the molecular method of polymerase chain reaction using sequence-specific primer amplification. The most frequent alleles included A*01, A*02, A*11 and A*24 at A locus, B*35 and B*40 at B locus and DRB1*07 and DRB1*15 in all the four groups, although the frequency fluctuated in individual communities. HLA-DRB1*03 was significantly high (P < 0.05) in the Sindhi. Phylogenetic association using neighbour-joining tree, based on DA genetic distances for HLA-A and HLA-B alleles, indicated that the Sindhis cluster with North Indian and Pakistan Sindhi. The three locus haplotype analysis revealed that A*02-B*40-DRB1*15 and A*33-B*44-DRB1*07 were common haplotypes in all the groups. The three locus haplotypes found suggest an influence from Caucasian and Oriental populations. The data will be useful in developing an umbilical cord stem cell panel in India. The results will have clinical implications in unrelated umbilical cord stem cell for transplantation in India.     

HLA and immunoglobulin polymorphisms in idiopathic dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is an idiopathic heart muscle disorder. The presence of circulating cardiac antibodies and the association with HLA-DR4 are consistent with autoimmune pathogenesis in a subset of patients. Sixty-eight DCM patients and 277 controls were typed for IgG heavy-chain constant region (Gm) and kappa light-chain (Km) allotypes. All patients and 210 of the 277 controls were HLA-DR typed. The Gm (1, 3, 17; 23; 5*, 21, 28) phenotype was overrepresented in DCM compared with controls (25% vs 13%, p = 0.0139, pc = NS, RR = 2.23). The frequency of this phenotype was higher in patients with younger age at onset, shorter symptom duration, and among those who were positive for cardiac as well as for non-organ-specific autoantibodies than in controls. A higher frequency of the Gm (1, +/- 2, 3, 17; +/- 23; 5*, 21, 28) heterozygous phenotypes was also found in DCM compared to controls (40.91% vs 26.89%; p = 0.02, pc = 0.04, RR = 1.88). The finding of Gm heterozygosity in DCM was associated with serum positivity for cardiac antibodies. A higher proportion of DCM patients were positive for both the Gm (1, 3, 17; 23; 5*, 21, 28) phenotype and HLA-DR4 compared to normals (3/68 vs 0/210; p = 0.04, RR = 22.50).(ABSTRACT TRUNCATED AT 250 WORDS)     

HLA class I polymorphisms in Tunisian patients with otosclerosis

Background: Otosclerosis is a common form of hearing impairment among Western-Eurasian adults. The cause of otosclerosis remains unknown. Autoimmune reaction against the otic capsule has been suggested as a possible aetiologic factor in otosclerosis.

Aim: The present study is the first report to evaluate the relationship between class I major histocompatibility complex (MHC) genes (HLA-A, HLA-B and HLA-Cw) and genetic susceptibility to otosclerosis in Tunisian patients.

Subjects and methods: Fifty unrelated Tunisian patients exhibiting clinical otosclerosis were typed for HLA-A, HLA-B and HLA-Cw antigens and compared with 100 ethnically-matched healthy controls.

Results: Increased frequencies of HLA-A*03 (OR = 4.16, Pc < 0.043), HLA-B*35 (OR = 2.76, Pc < 0.043) and HLA-Cw*03 (OR = 4.57, Pc < 0.043) antigens were found in the patients with otosclerosis compared with healthy controls. Individuals with HLA-A*30 (OR = 0.25, Pc < 0.043), HLA-B*51 (OR = 0.11, Pc < 0.043), HLA-Cw*16 (OR = 0.08, Pc < 0.043) and Cw*06 (OR = 0.32, Pc < 0.043) antigens have a protective effect against otosclerosis.

Conclusions: In conclusion, the data suggest that a variation in class I HLA antigens could be a genetic factor involved in susceptibility to otosclerosis in the Tunisian population.     

HLA polymorphisms in a Han Chinese population of Sichuan

This study reports the phenotype frequencies (PF) and gene frequencies (GF) of a homogeneous Sichuan Han Chinese population by typing of unrelated 229 individuals and 16 families for HLA-A, B, C, DR and DQ antigens. The frequencies of Bw67, Bw71, DRw12, DRw13 and DRw14 are the first to be reported in Chinese. Two two-locus haplotypes with significant linkage disequilibrium among the Sichuan have also been listed.     

HLA and KIR polymorphisms affect NK-cell anti-tumor activity

Killer cell immunoglobulin-like receptors (KIRs) and their cognate human leukocyte antigen (HLA) ligands are key to the maintenance of natural killer (NK) cell tolerance. The gene complexes encoding both KIRs and HLA ligands are extremely polymorphic. Because the extent of NK cell inhibition varies with the allelic forms expressed, NK cell tolerance can be broken more easily in some individuals than in others. This explains why particular combinations of KIR and HLA genes are associated with an increased risk of autoimmune diseases or with more efficient antiviral responses. Breaking of NK cell tolerance might be prerequisite to kill leukemic blasts. At present, there are ample indications that NK cells can eradicate acute myeloid leukemia blasts in patients with a favorable combination of HLA and KIR genes. Selecting these individuals for clinical trials should give insight into the feasibility of anti-tumor therapy mediated through NK cells.     

DQCAR microsatellite polymorphisms in three selected HLA class II-associated diseases

Abstract: DQCAR is a very polymorphic CA repeat microsatellite located between the HLA DQA1 and DQB1 gene. Previous studies have shown that specific DQCAR alleles are in tight linkage disequilibrium with known HLA DR-DQ haplotypes. Of special interest was the fact that haplotypes containing long CA repeat alleles (DQCAR > 111) were generally more polymorphic within and across ethnic groups. In these latter cases, several DQCAR alleles were found even in haplotypes containing the same flanking DQA1 and DQB1 alleles. In this work, three HLA class II associated diseases were studied using the DQCAR microsatellite. The aim of this study was to test if DQCAR typing could distinguish haplotypes with the same DRB1, DQA1 and DQB1 alleles in control and affected individuals. To do so, patients with selected HLA DR-DQ susceptibility haplotypes were compared with HLA DR and DQ matched controls. This included: Norwegian subjects with Celiac disease and the HLA DRB1*0301, DQA1*05011, DQB1*02 haplotype; Japanese subjects with Type 1 (insulin-dependent) Diabetes Mellitus and the HLA DRB1*0405, DQA 1*0302, DQB 1*0401 haplotype; and French patients with corticosensitive Idiopathic Nephrotic Syndrome and the HLA DRB 1*0701, DQA 1*0201, DQB1*0202 haplotype. These specific haplotypes were selected from our earlier work to include one haplotype bearing a short DQCAR allele (celiac disease and DR3, DQ2-DQCAR99) and two haplotypes bearing long DQCAR alleles (Diabetes Mellitus and DR4, DQ4-DQCAR 113 or 115 Idiopathic Nephrotic syndrome and DR7, DQ2-DQCAR 111–121). Additional DQCAR diversity was found in both control and patients bearing haplotypes with long CA repeat alleles. The results indicate that DQCAR typing did not improve specificity in combination with high resolution DNA HLA typing as a marker for these three disorders.     

HLA class I and class II polymorphisms in Tunisian Berbers

Background: The HLA polymorphism is a powerful genetic tool to study population origins. By analysing allele frequencies and haplotypes in different populations, it is possible to identify ethnic groups and establish the genetic relationships among them.

Aim: The Berber (endogenous Tunisians) HLA class I and class II genotypes were analysed and compared with those of Mediterranean and Sub-Saharan African communities using genetic distances, Neighbour-Joining dendrograms, correspondence and haplotype analysis.

Subjects and methods: One hundred and five unrelated Berbers were typed for HLA class I (A, B) and class II (DRB1, DQB1) gene alleles using reverse dot-blot hybridization.

Results: High frequencies of A*0201 (24.76%), A*3402 (22.38%) and B*44 (32.85%) alleles were recorded for Berbers, the highest recorded for Mediterranean and North African populations. This study shows a close relatedness of Tunisian Berbers to other Tunisians, North Africans and Iberians.

Conclusion: The apparent relatedness of Tunisian Berbers to present-day (North African) Tunisians, Algerians and Moroccans suggests that the Arab invasion of North Africa (7^th–11^th centuries AD) did not significantly impact the genetic makeup of North Africans. Furthermore, Tunisian Berbers appear to be closely related to Iberians (Spaniards and Basques), indicating that the 7^th century AD gene flow of invaders was low in Iberians and that the main part of their genetic pool came after the Northward Saharan migration, when hyper-arid conditions were established in Sahara (before 6000 BC). Other studied populations belong to the old Mediterranean substratum, which has been present in the area since pre-Neolithic times. This study indicates a higher proportion of Iberian than Arab ancestry in Tunisian Berbers, which is of value in evaluating the evolutionary history of present-day Tunisians. Greeks seem to share genetic HLA features (Chr 6) with Sub-Saharans. The relatedness of Greeks to Sub-Saharans has been confirmed by other studies based on chromosome 7 genetic markers.     

HLA polymorphisms in Italian bone marrow donors: a regional analysis

Abstract: The aim of this study was to analyse the genetic structure of the Italian bone marrow donor population on the basis of HLA polymorphisms. Maximum likelihood estimates of gene and haplotype frequencies, goodness of fit to Hardy-Weinberg predictions and heterozygosity were calculated for 18 Italian administrative regions. Moreover, the phenotypic peculiarity of the regional populations was assessed by analysing the number of "typical phenotypes" found in each region. Multivariate analyses carried out on HLA-A and HLA-B gene frequencies gave a genetic pattern of the donor pools that reflects the structure of the Italian population determined in previous population genetic studies. Sardinia shows a very large genetic difference with respect to the other regions; of these, the central-southern regions are well-differentiated from the central-northern. Southern regions present higher genetic heterogeneity and a higher probability of providing donors with phenotypes not already present in the Italian bone marrow registry. The large sample size of the bone marrow donor registry allowed us to estimate gene and haplotype frequencies with greater accuracy than in previous studies. Our results may be of use in determining strategies for donor recruitment and selecting unrelated donors for patients requiring bone marrow grafting, as well as for anthropological, epidemiological and population genetics studies.     

Autoimmunity, HLA, Gm and Km polymorphisms in Turner's syndrome

Considering the high frequency of autoimmune disorders in Turner's syndrome and the close relationship between autoimmunity, HLA and immunoglobulin constant region gene polymorphisms, we studied 46 patients with Turner's syndrome, by determination of autoantibodies, HLA histoglobulins and Gm and Km allotypes. OSA and in particular PCA resulted significantly more frequent in patients than in the controls. A higher frequency of HLA-A31, B38 antigens and of blanks at HLA-A locus was found in Turner's subjects than in the controls. A31 was significantly more frequent in autoantibody positive patients while B38 was more frequent in autoantibody negative Turner's subjects than in the controls. DR4 antigen was present only in autoantibody negative patients. Gm 3; 23; 5* phenotype was significantly less frequent, while Gm 3;..; 5* phenotype was more frequent in patients than in controls. Our data confirm the higher incidence of autoimmunity disorders in Turner's syndrome than in normal subjects. Particular HLA and immunoglobulin types seem to mark this condition. The increase in the blank frequency at A locus could be explained by the presence of a rare antigen at HLA-A locus or a particularly elevated homozygous condition in these subjects.     

MICB polymorphisms and haplotypes with MICA and HLA alleles in Koreans

Major histocompatibility complex (MHC) class I chain-related gene B (MICB) is located within the human MHC class I region. The location of MICB in the MHC region may imply the presence of linkage disequilibrium with polymorphic MICA and human leukocyte antigen (HLA) loci. MICB is also polymorphic; however, MICB polymorphisms have not been investigated in Koreans. Using sequence-based typing (SBT), we estimated the allelic frequencies of MICB and haplotypes with MICA, HLA-B, and HLA-DRB1 at high resolution in a population of 139 unrelated Korean individuals. Eight MICB alleles were identified. The most frequent allele was MICB*005:02/*010 (57.2%), followed by *002 (11.5%), *004 (8.3%), *005:03 (8.3%), and *008 (6.8%). The most common two-locus haplotypes were MICB*005:02/*010-MICA*010 (19.4%), MICB*005:02/*010-DRB1*15:01 (6.5%), and MICB*005:02/*010-B*15:01 (10.4%); the most common three-locus haplotypes were B*15:01-MICA*010-MICB*005:02/*010 (5.8%) and MICA*010-MICB*005:02/*010-DRB1*04:06 (10.4%); and the most common four-locus haplotype was B*15:01-MICA*010-MICB*005:02/*010-DRB1*04:06 (5.8%). This is the first study to provide information about MICB allele frequencies and haplotypes with HLA in Koreans. These study results should help understand mechanisms of disease association between the MICB locus and neighboring loci in Koreans.     

Lymphoreticular diseases in Nigerians

Background

The lymphoreticular system plays a major role in both the innate and adaptive immune responses. This study reviews retrospectively cases of lymphoreticular diseases seen at a tertiary institution in Nigeria.

Materials and Methods

This is a retrospective study in which biopsies from the bone marrow, spleen, lymph nodes and extranodal lymphoid tissues reported within a period of 16 years were reviewed with respect to age, sex and pathological diagnosis. Statistical analysis was performed for differences in proportion using Chi square by SPSS version 12.

Results

Nine hundred and forty four cases comprising 559 biopsies from lymph nodes and extranodal lymphoid tissues, 272 bone marrow biopsies and 113 spleen biopsies were studied. Non Hodgkin''s lymphoma (NHL) and tuberculosis were the most common lesions in lymph nodes and extranodal lymphoid tissues. The axillary and cervical nodes accounted for most cases of metastasis. Breast cancer accounted for the majority of metastasis to lymph nodes.The most common pathological changes in bone marrow were NHL and reactive hyperplasia. Patients with chronic lymphocytic leukaemia (CLL) had the highest mean age, which was significantly higher than in those with NHL (p=.001, 95% confidence interval −27.91 to −7.76). The most common finding in the spleen was splenic rupture and haemoperitoneum from road traffic accident.

Conclusion

NHL and tuberculosis should be high on the list of differential diagnosis of lymphadenopathy in Nigerians. Whereas trauma from RTA was the major reason for splenectomy in Nigerians, in the elderly splenic biopsy would likely show CLL.