Clinical Relevance of Pretransplant HLA Class II Donor-specific Antibodies in Renal Transplantation Patients with Negative T-cell Cytotoxicity Crossmatches

BACKGROUND: We evaluated the clinical relevance of pretransplant donor-specific HLA antibodies (DSA) in renal transplantation patients who had negative T-cell cytotoxicity crossmatches. METHODS: From 328 consecutive renal transplant recipients, we selected 28 patients who had positive pretransplant (historical or at the time of transplantation) flow cytometry crossmatches, but negative T-cell cytotoxicity crossmatches at the time of transplantation. The presence of DSA and its level at the time of transplantation were retrospectively tested using Luminex single antigen assays. RESULTS: DSA was present in 16 (57.1%) of 28 patients. Biopsy-proven acute rejection (9 patients) occurred more frequently in patients with DSA than in those without DSA (56.3% vs. 0.0%; P=0.003). The positivity rate of class II DSA was significantly higher in patients with antibody-mediated rejection (AMR) than in those without AMR (100% vs. 21.7%; P=0.003). However, the positivity rate of class I DSA was not different between the two groups (40% vs. 40.9%). Among patients with class II DSA, those with AMR tended to have higher antibody levels (median fluorescence intensity, MFI) than those without AMR (16,359 vs. 5,910; P=0.056). A cut-off MFI value of 4,487 for class II DSA predicted the occurrence of AMR with good sensitivity and specificity (100% and 87.0%). CONCLUSIONS: In patients with negative T-cell cytotoxicity crossmatches, the presence of class II DSA and its level at the time of transplantation were associated with the occurrence of AMR. Pretransplant DSA measurement with Luminex single antigen assay would be useful in renal transplantation.

Asociación de la tuberculosis pulmonar con los antígenos del sistema HLA en el Noreste de México / Association of pulmonar tuberculosis with HLA system antigens in Northeastern Mexico

Antecedentes: La susceptibilidad genética a tuberculosis pulmonar (TbP) ha sido asociada al sistema HLA (antígenos de los leucocitos humanos) del MHC (complejo mayor de histocompatibilidad), principalmente con los antígenos HLA-DR y -DQ. Dado lo anterior, el objetivo de este estudio caso-control no pareado, fue determinar la asociación de TbP con los antígenos HLA-DR y -DQ en pacientes que asistían a una unidad médica del IMSS. Métodos: Los fenotipos del sistema HLA de casos (n=50) y controles (n=417), se definieron serológicamente por la técnica de microlinfocitotoxicidad dependiente de complemento. Los linfocitos B fueron obtenidos utilizando inmunoperlas. Las frecuencias alélicas y haplotípicas, equilibrio de Hardy-Weinberg y el desequilibrio de ligamiento, se determinaron mediante el programa computacional Arlequín versión 3.01, y el riesgo relativo (RR) mediante el programa Epimax Table Calculator. Resultados: Los alelos HLA-DR11(5), -DR16(2) y -DQ7(3) y los haplotipos /DR11(5)-DQ7(3), /DR14(6)-DQ5(1) y /DR16(2)-DQ7(3) fueron más frecuentes en casos que en controles (RR>1, p<0.05). Los alelos HLA-DR17(3) y DQ8(3) y los haplotipos /DR17(3)-DQ2 y /DR4-DQ8(3) fueron más frecuentes en controles que en casos (RR<1, p<0.05). Conclusiones: Estos resultados sugieren asociación entre TbP y HLA-DR y -DQ en esta población mestiza mexicana y son similares a los encontrados en otros estudios caso-control no pareados a nivel mundial.

BACKGROUND: Genetic susceptibility to pulmonary tuberculosis (PTb) has been associated with the HLA (Antigens of the Human Leukocytes) system of the MHC (Major Histocompatibility Complex), mainly with HLA-DR and-DQ antigens. Based on this assumption we carried out a case control study to determine the association of PTb with the HLA-DR and-DQ antigens among a sample of patients attending a medical unit belonging to the Mexican Social Security System (IMSS). METHODS: HLA system phenotypes from cases (n=50) and controls (n=417), were defined serologically using a complement dependent microlymphocytotoxic assay. B lymphocytes were obtained using immunobeads. The allele and haplotype frequencies were determined using the Arlequin version 3.01 computer software. Relative risk (RR) was calculated with the Epimax Table Calculator. RESULTS: The alelles HLA-DR11(5), -DR16(2) and -DQ7(3) and haplotypes /DR11(5)-DQ7(3), /DR14(6)-DQS(1) and /DR16(2)-DQ7(3) had a higher frequency in cases than in controls (RR>1, p<0.05). The HLA-DR17(3) and DQ8(3) alelles and /DR17(3)-DQ2 and /DR4-DQ8(3) haplotypes had a higher frequency among controls than among cases (RR<1, p<.05). CONCLUSIONS: These results indicate an association between PTb with the HLA-DR and -DQ antigens in a Mexican sample. Our results are similar to those found in the international literature.

Marcadores genéticos e auto-imunes do diabetes melito tipo 1: da teoria para a prática: [revisão] / Genetic and humoral autoimmunity markers of type 1 diabetes: from theory to practice: [review]

O diabetes melito tipo 1 auto-imune (DM1A) resulta da destruição auto-imune seletiva das células-beta pancreáticas produtoras de insulina. O principal determinante genético de suscetibilidade para o DM1A está em genes do complexo principal de histocompatibilidade, no cromossomo 6p211.3 (locus IDDM1), responsável por 40 por cento ou mais da agregação familiar dessa doença. O maior risco é conferido pelo genótipo do antígeno leucocitário humano HLA-DR3-DQA1* 0501-DQB1*0201/DR4-DQA1*0301-QB1*0302, e o haplótipo HLA-DR15-DQA1* 0102-DQB1*0602 é associado à proteção. Três outros loci relacionados à predisposição a DM1A são o número variável de freqüências repetidas (VNTR) do gene da insulina (IDDM2), que confere 10 por cento da suscetibilidade genética, o antígeno-4 associado ao linfócito T citotóxico (CTLA-4) e o protein tyrosine phosphatasis nonreceptor-type 22 (PTPN22). Muitos outros genes suspeitos de predispor à auto-imunidade estão sendo investigados. O DM1A é freqüentemente associado com doença auto-imune tiroidiana, doença celíaca, doença de Addison e várias outras doenças auto-imunes, caracterizadas por auto-anticorpos órgãos-específicos, relacionados aos mesmos determinantes genéticos. Esses anticorpos são úteis na detecção de auto-imunidade órgão-específica antes do aparecimento da doença clínica, prevenindo comorbidades.

Type 1 A diabetes mellitus (T1AD) results from the autoimmune destruction of the insulin producing pancreatic beta-cells. The largest contribution to genetic susceptibility comes from several genes located in the major histocompatibility complex on chromosome 6p21.3 (IDDM1 locus), accounting for at least 40 percent of the family aggregation of this disease. The highest-risk human leukocyte antigen HLA genotype for T1AD is DR3-DQA1*0501-DQB1*0201/DR4-DQA1*0301-DQB1*0302, whereas -DR15-DQA1*0102-DQB1*0602 haplotype is associated with dominant protection. Three other T1D loci associated with predisposition are the Variable Number for Tandem Repeats (VNTR) near the insulin gene (IDDM2), which accounts to 10 percent of genetic susceptibility, the Cytotoxic T-Lymphocyte-associated Antigen (CTLA-4)(IDDM 12) and the Protein Tyrosine Phosphatasis Nonreceptor-type 22 (PTPN22). Many other gene suspected to predispose to autoimmunity have been investigated. T1AD is frequently associated with autoimmune thyroid disease, celiac disase, Addison´s disease and many other autoimmune diseases, characterized by organ-specific autoantibodies and related to the same genetic background. Using these autoantibodies, organ specific autoimmunity may be detected before the development of clinical disease preventing significant morbidity.

HLA-DRB1, DQA1 and DQB1 alleles and haplotypes frequencies in Iranian healthy adult responders and non-responders to recombinant hepatitis B vaccine

Different studies have demonstrated that a small proportion of healthy individuals receiving the hepatitis B [HB] vaccine do not produce protective levels of anti-HB antibody, a phenomenon which could be linked to certain human leukocyte antigen [HLA] class-II alleles or haplotypes. The present study was undertaken to determine the frequency of HLA class-II alleles in Iranian healthy adult responders and non-responders to HB vaccine. Twelve non-responders [anti-HBs antibody < 10 IU/L] and 46 responders [anti-HBs antibody > 100 IU/L] were tissue typed for HLA class-II. HLA-DRB1, DQB1 and DQA1 alleles were determined using polymerase chain reaction based on sequence specific primers [PCR-SSP] technique. Accessibility to excess amount of genomic DNA was possible using Epstein-Barr virus [EBV]-transformed B-cells established from all vaccinees. Our results demonstrated increased frequencies of HLA- DRB1*07, DRB1*03, DRB1*04, DQB1*0201, DQA1*0201 alleles and HLA- DRB1*07/DQB1*0201/DQA1*0201 and DRB1*04/DQB1*0302/DQA1*03011 haplotypes in the non-responder group. Comparison between responders and non-responders revealed only a significant difference for DQB1*0201 allele [p < 0.05]. These findings confirm the association of certain HLA alleles and haplotypes with the lack of antibody response to HB vaccine in an Iranian population

A study of T CD4, CD8 and B lymphocytes in narcoleptic patients / Estudo dos linfócitos T CD4, CD8 e B em pacientes com narcolepsia

Narcolepsy is characterized by excessive daytime sleep and cataplexy. Little is known about the possible difference in pathophysiology between patients with or without cataplexy. OBJECTIVE: To quantify T CD4, T CD8 and B lymphocytes in subgroups of patients with narcolepsy and the presence or absence of the HLA-DQB1*0602 allele between groups. METHOD: Our study was prospective and controlled (transversal) with 22 narcoleptic patients and 23 health control subjects. Patients underwent an all-night polysomnographic recording (PSG) and a multiple sleep latency Test (MSLT). The histocompatibility antigen allele (HLA-DQB1*0602), T CD4, CD8 and B lymphocytes were quantified in control subjects and in narcoleptics. RESULTS: The HLA-DQB1*0602 allele was identified in 10 (62.5 percent) of our 16 cataplexic subjects and in 2 (33.3 percent) of the 6 patients without cataplexy (p=0.24). In control subjects, HLA-DQB1*0602 allele was identified in 5 (20 percent). A significant decrease in T CD4 and B lymphocytes was found in narcoleptic patients with recurrent cataplexy when compared with our patients without cataplexy. CONCLUSION: Autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis were associated with a decrease in sub-group of T CD4 and B lymphocytes. A drop in B lymphocytes count in reumathoid arthritis might, it is posited, be correlated to the presence of HLA-DRB1 allele along with an overall worsened outcome of the affliction. The theory of an increase in consumption of B lymphocytes over the maturation phase has likewise been put forward. Our study reinforces the view that narcolepsy should be considered from an immunological perspective.

A narcolepsia é caracterizada por sonolência excessiva diurna e cataplexia. Pouco se sabe sobre as diferenças fisiopatológicas entre pacientes com e sem cataplexia. OBJETIVO: Quantificar os linfócitos T CD4, T CD8 e B e a presença do alelo HLA-DQB1*0602 nos subgrupos de pacientes com narcolepsia. MÉTODO: O estudo foi prospectivo e controlado (transversal) com 22 pacientes portadores de narcolepsia e 23 sujeitos controle. Os pacientes realizaram polissonografia (PSG) de noite inteira e teste de múltiplas latências do sono (TMLS). O alelo do antígeno de histocompatibilidade (HLA-DQB1*0602) e os linfócitos T CD4, T CD8 e B foram quantificados nos pacientes e sujeitos controle. RESULTADOS: O alelo HLA-DQB1*0602 foi encontrado em 10 (62,5 por cento) dos 16 pacientes com cataplexia e em 2 (33,3 por cento) dos 6 pacientes sem cataplexia (p=0,24). Nos sujeitos controle, o alelo HLA-DQB1*0602 foi encontrado em 5 sujeitos (20 por cento). Um aumento significativo de linfócitos T CD4 e uma diminuição de linfócitos B foi observado no grupo de pacientes com cataplexia freqüente quando comparado ao grupo de pacientes sem cataplexia. CONCLUSÃO: Doenças auto-imunes como lupus eritematoso sistêmico e artrite reumatóide têm sido associadas com diminuição de linfócitos T CD4 e B. Na artrite reumatóide, diminuição de linfócitos B e presença do alelo HLA-DRB1 tem sido associada a pior evolução. Para essa doença, a teoria de um maior consumo de linfócitos B em suas fases de maturação tem sido aventada. Os achados do nosso estudo reforçam a teoria imunológica da narcolepsia.

Estudo comparativo entre reação de Mitsuda e antígenos leucocitários humanos em pacientes hansenianos / Comparative study between the Mitsuda test and the human leukocyte antigens in leprosy patients

Neste estudo, propomos comparar o teste cutâneo de Mitsuda e os alelos HLA-DR2/HLA-DR3 e HLA-DQ1 relacionados com as formas clínicas da hanseníase em 176 pacientes (50 TT, 50 LL e 76 B). Os resultados obtidos não revelaram associação entre reação de Mitsuda e os alelos HLA nas formas clínicas isoladas; no entanto, quando analisados de acordo com a resposta ao teste de Mitsuda, associação significativa foi encontrada entre os pacientes Mitsuda negativos e HLA-DQ1 (p=0,002). Não foi observada associação entre reação de Mitsuda positiva e alelos HLA-DR2/DR3. Concluímos que existe importante participação do alelo HLA-DQ1 na ausência de resposta ao teste de Mitsuda. Sugerimos estudos mais específicos para este alelo.

In this study, we aimed to compare the Mitsuda skin test with the alleles HLA-DR2/HLA-DR3 and HLA-DQ1, in relation to the clinical forms of leprosy in 176 patients (50 TT, 50 LL and 76 B). The results obtained did not reveal any association between the Mitsuda reaction and the HLA alleles in the clinical forms isolated. However, when analyzed according to Mitsuda test response, a significant association was found between patients with negative Mitsuda reaction and HLA-DQ1 (p=0.002). No association was observed between positive Mitsuda reaction and the HLA-DR2/DR3 alleles. We concluded that the allele HLA-DQ1 has an important participation when there is no response to the Mitsuda test. We suggest that more specific studies should be developed on this allele.

Diagnosis of celiac disease.

Celiac disease is an immune mediated enteropathy initiated by ingestion of gluten, in genetically susceptible individuals. With changing epidemiology, celiac disease initially thought to affect only Europeans, has been increasingly reported from other parts of the world including India. However, its true prevalence in India is still not known, as the diagnosis is being missed. The gold standards for diagnosis have been characteristic small intestinal mucosal changes on gluten and a full clinical remission on its removal from the diet. Presence of serological antibodies, which disappear on gluten free diet further confirms the diagnosis. The understanding of the histopathology of celiac disease has changed over the years. The small bowel mucosal lesion of celiac disease is an evolutionary process with normal mucosal architecture and an increase in intraepithelial lymphocytes at one end of the spectrum and classical flat mucosa at the other. In the Indian subcontinent celiac disease has a heterogeneous histological presentation and the diagnosis may be missed if it is based only on severe mucosal changes or the serology is not considered when moderate or mild mucosal changes are present. The last two decades have shown that antiendomysical (Anti EMA) and anti tissue transglutaminase antibodies (anti-tTGA) have a sensitivity and specificity of more than 95% to diagnose celiac disease. Anti EMA tests being operator dependent are more liable to errors and anti- tTGA may be preferred for large scale screening. However, the different source of tTGA antigen, varied techniques of production and the use of arbitrary units by different commercial kits can influence the diagnostic accuracy of the anti-tTGA assay. There is a strong genetic association of celiac disease with HLA-DQ2 or DQ8. The presence of HLA-DQ2 hetrodimer in more than 97% of a group of North Indian patients with celiac disease indicates that this population has a similar genetic risk for the disease. HLA DQ2 typing can be used for ruling out celiac disease where the diagnosis is equivocal as it has a negative predictive value of greater than 95%. Given the protean clinical manifestation and the heterogeneous histology a standard algorithm for diagnosis of celiac disease is important.

Aspectos genéticos e imunopatogênicos da doença celíaca: visão atual / Genetics and immunopathogenics aspects of the celiac disease: a recent vision

RACIONAL: A doença celíaca ou enteropatia por sensibilidade ao glúten, é uma forte condição hereditária. Embora a associação genética da doença celíaca com os haplótipos HLA-DQ2 e DQ8 seja conhecida há muito tempo, outros genes HLA e não-HLA também são importantes no desenvolvimento da afecção. A doença celíaca resulta de um efeito combinado de produtos de diferentes genes funcionantes normalmente. A lesão intestinal é imunologicamente mediada e múltiplos mecanismos efetores são responsáveis pela sua expressão. A interação entre fatores genéticos, imunológicos e ambientais explicam o amplo espectro de alterações clínicas, histológicas e sorológicas observadas nos diferentes estágios de desenvolvimento da doença, ressaltando a natureza poligênica da mesma. CONCLUSAO: Os avanços recentes na compreensão da imunopatogenia, genética e diagnóstico da doença celíaca têm permitido que rígidos conceitos e critérios pré-estabelecidos sejam revistos e adequados às novas evidências, visando melhor diagnóstico e orientação para pacientes celíacos e familiares.

Determinação de autoanticorpos para antígenos da mielina no soro de pacientes HLA - DQB1*0602 com esclerose múltipla / Determination of autoantibody for myelin antigens in the serum of patients HLA - DQB1*0602 with multiple sclerosis

Esclerose múltipla (EM) é doença inflamatória desmielinizante do sistema nervoso central (SNC) de natureza autoimune, mediada por linfócitos Th1. A produção de autoanticorpos séricos para proteína básica da mielina (MBP), proteolipídeo PLP e sequência da glicoproteína de oligodendrócito MOG 92-106, foi determinada em 54 indivíduos saudáveis e 26 pacientes com EM expressando ou não o alelo de suscetibilidade HLA-DQB1*0602. Independentemente da expressão do alelo DQB1*0602, todos os pacientes apresentaram produção marcante (p< 0,0001) de autoanticorpos isotipo IgG para MBP e MOG 92-106, e do isotipo IgA para PLP e MOG 92-106. Os resultados sugerem que outros alelos HLA da classe II exerçam influência na suscetibilidade à EM e no reconhecimento imunológico dos antígenos encefalitogênicos, determinando o padrão de resposta autoimune e contribuindo na manutenção e/ou controle da inflamação no SNC

Study of HLA-A, B, C, DR, DQ profile of patients with established rheumatic heart disease in Kashmir.

This study included 54 unselected patients with rheumatic heart disease (RHD) with or without history of rheumatic fever and 224 control subjects, all Kashmiris. HLA-A19 was increased in 42.59 percent of patient population as against 23.66 percent of controls, with a relative risk of 2.39. HLA-DR4 was positive in 56 percent of patients as against 31.69 percent in controls with a relative risk of 2.74. DQ3 was also present in 72 percent of patient population as against 50.7 percent of controls. These findings suggest a genetic predisposition to rheumatic fever/RHD. More family studies are warranted.