Genetic determinants of 21-hydroxylase autoantibodies amongst patients of the Type 1 Diabetes Genetics Consortium.

BACKGROUND: Autoantibodies to 21-hydroxylase (21OH-AA) precede the onset of autoimmune Addison's disease (AD) and are found in 1.5% of individuals with type 1 diabetes mellitus (T1DM). The greatest genetic risk for both disorders is found in the major histocompatibility complex (MHC), suggesting a common pathophysiology between AD and T1DM. Screening for 21OH-AA in newly diagnosed T1DM patients is a valuable prognostic tool, made stronger when MHC genotype is considered. METHODS: The Type 1 Diabetes Genetics Consortium has collected genotype data in T1DM subjects with tissue-specific autoantibody typing. Genotype and phenotype data in individuals positive and negative for 21OH-AA are compared. RESULTS: Major genetic risk for 21OH-AA is in the MHC haplotypes DRB1*04-DQB1*0302 (primarily DRB1*0404) and DRB1*0301-DQB1*0201. Protective effects in class II MHC haplotypes DRB1*0101-DQB1*0501 and DRB1*0701-DQB1*0202 also were detected. There is no difference in the presence of HLA-B15 and little difference in the presence of HLA-B8 (after class II effects are accounted for) in T1DM patients with 21OH-AA compared with known associations (HLA-B8 positive and HLA-B15 negative) in AD. CONCLUSIONS: In 21OH-AA(+) subjects, genetic risk is found mainly in MHC class II haplotypes DR3 and DR4 but not class I alleles (HLA-B8 or HLA-B15). This suggests a difference between autoantibody formation (class II dependent) and progression to overt disease (class I dependent) in AD.

Role of cytotoxic T-lymphocyte-mediated immune selection in a dominant human leukocyte antigen-B8-restricted cytotoxic T-lymphocyte epitope in Nef.

OBJECTIVES: To study the role of cytotoxic T-lymphocyte (CTL) escape for disease progression in HIV-1 infection, we analyzed the CTL response to the dominant human leukocyte antigen (HLA)-B8-restricted CTL epitope FLKEKGGL (FL8) in HIV-1 Nef. METHODS: HIV-1 nef genes derived from 56 patients were analyzed by polymerase chain reaction (PCR)-based sequencing. T-cell responses against FL8 and mutated FL8 variants were detected by gamma-interferon (gamma-IFN) enzyme linked immunospot (ELISPOT) assay. RESULTS: The longitudinal analysis of an HIV-1-infected patient with good control of HIV-1 viremia for several years demonstrated an association of rising viremia with the emergence of CTL escape mutations within the HLA-B8-restricted Nef-specific CTL epitopes FLKEKGGL and WPAIRERM. Analysis of nef genes in 56 HIV-1-infected patients demonstrated a significant correlation between the occurrence of mutations in the FL8 epitope and the presence of HLA-B8. The mutations within the FL8 epitope could decrease CTL recognition; however, there was strong variation regarding the recognition of viral variants between individual donors. The presence of FL8 mutations was associated with lower CD4 cell counts and higher viral loads. CONCLUSIONS: Our data demonstrate a strong CTL selection pressure on the immunodominant HLA-B8-restricted CTL epitope FL8 in HIV-1 Nef. The association of FL8 mutations with lower CD4 cell counts indicates an important role of CTL escape mutations for disease progression.

HLA and smoking in prediction and prognosis of small cell lung cancer in autoimmune Lambert-Eaton myasthenic syndrome.

Patients with small cell lung cancer (SCLC) survive longer if they have the antibody-mediated Lambert-Eaton myasthenic syndrome (LEMS), making this autoimmune disorder a prototype disease for studying cancer immunosurveillance. Patients with nontumor LEMS (NT-LEMS) never develop SCLC but are otherwise indistinguishable clinically. Therefore, we have compared immunogenetic factors in SCLC-LEMS and NT-LEMS and studied their role in the pathogenesis of LEMS and survival from SCLC. In 48 British and 29 Dutch Caucasian LEMS patients, we studied clinical symptoms, antibody titers, HLA types and alleles at six nearby located microsatellite loci. Highly significant associations were found in NT-LEMS, which appeared strongest with HLA-B8, but also involved HLA-DQ2, -DR3 and six flanking microsatellite alleles. SCLC-LEMS patients were not different from controls. Smoking was a strong predictor of SCLC. In contrast, HLA-B8 positivity correlated with a decreased risk of SCLC even among the smokers. Moreover, in SCLC-LEMS patients, HLA-B8 positivity correlated with prolonged survival after LEMS onset. We propose that two distinct immunopathogenetic routes can lead to one clinically and serologically indistinguishable autoimmune myasthenic syndrome. HLA-DR3-B8 is strongly associated with LEMS in nontumor patients only. In other LEMS patients, SCLC apparently provides a powerful autoimmunogenic stimulus that overrides HLA restrictions in breaking tolerance to calcium channels. Moreover, negativity for HLA-B8 combined with smoking behavior points more strongly to an underlying SCLC and predicts a worse prognosis in SCLC-LEMS patients.

Individual susceptibility to hexavalent chromium of workers of shoe, hide, and leather industries. Immunological pattern of HLA-B8, DR3-positive subjects.

BACKGROUND: This study was designed to examine the effects of hexavalent chromium [Cr(VI)] on the immunological pattern of shoe, hide, and leather industry workers, moving from the hypothesis that some haplotypes (HLA-B8,DR3) can be important hidden risk cofactors. METHODS: Workplaces of 20 firms were monitored for total and respirable dusts and for total and hexavalent chromium. Cr(VI) on materials was also measured. Assay of chromium levels in blood and urine of 44 serological human leukocytes antigen (HLA)-typed workers (20 exposed, 15 HLA-B8,DR3-negative/5-positive and 24 non-exposed, 18 HLA-B8,DR3-negative/6-positive subjects) was performed by atomic absorption, and lymphocyte subsets (FACS-analysis), mitogen-mediate lympho-proliferation ([3H]thymidine incorporation), cytokine levels (ELISA), natural killer (NK) cytotoxic activity (51Cr-release assay) were determined. RESULTS: The environmental parameter levels are lower than threshold limit value-time-weighted average (TLV-TWA); in the materials, the Cr(VI) values exceeded the levels allowed. The peripheral blood mononuclear cells (PBMC) proliferation and the T-helper1 (TH1) cytokine pattern of subjects chronically exposed were significantly raised; addition in vitro of Cr(VI) further stimulated these parameters and in general the entire TH1 system and NK activity. The TH2 system was unaltered. In the HLA-B8,DR3-positive workers, immunologically "low responders", the addition of Cr(VI) in vitro caused a further reduction of the considered parameters in the exposed subjects with a dramatic deficit of the TH1 system. CONCLUSIONS: Results indicate the unsuitability of TLV-TWA as a line of demarcation between safe and dangerous Cr(VI) concentrations and the importance of individual genetic susceptibility for occupational and preventative medicine. In particular, the presence of the HLA-B8,DR3 alleles can represent an important cofactor of immunotoxic susceptibility consequent to chronic low-dose Cr(VI) exposure.

Distribution of HLA class I alleles differs in celiac disease patients according to age of onset.

Celiac disease (CD) or gluten-sensitive enteropathy is strongly associated with HLA-DQ alleles; more than 95% of patients are DQB1*02. However, the uniform association with HLA-DQ alleles does not explain the clinical heterogeneity, especially the wide range in the age of onset of CD. We asked whether the age of onset of CD is also influenced by class I genes of the human MHC. We performed HLA typing in three groups of patients suffering from CD. The age of onset in the first group (N = 200) was before 15 years of age, in the second group (N = 62) between 15 and 40 years, in the third group (N = 59) after 40 years. We observed a statistically significant increase in the frequencies of HLA-B8 and Cw7 with increasing age of onset. In conclusion, we conclude that distinct alleles from the class I region of the human MHC might lead to late onset of CD. In particular, relatives of CD patients with the disease-prone HLA class I alleles HLA-B8 and Cw7 should be followed up carefully for late onset of CD.

Clonal selection, clonal senescence, and clonal succession: the evolution of the T cell response to infection with a persistent virus.

We have analyzed the CD8(+) T cell response to EBV and find that a larger primary burst size is associated with proportionally greater decay during the development of memory. Consequently, immunodominance and clonal dominance are less marked in memory than primary responses. An intuitive interpretation of this finding is that there is a limit to the number of cell divisions a T cell clone can undergo, and that the progeny of clones that have expanded massively during a primary immune response are more prone to die as a result of senescence. To test this hypothesis, we have derived a mathematical model of the response of different T cell clones of varying avidity for Ag in the primary and persistent phases of viral infection. When cellular survival and replication are linked to T cell avidity for Ag and Ag dose, then high-avidity T cells dominate both the primary and secondary responses. We then incorporated a limit in the number of cell divisions of individual T cell clones to test whether such a constraint could reproduce the observed association between cell division number and alterations in the contribution of clones to the response to persistent infection. Comparison of the model output with the experimental results obtained from primary and persistent EBV infection suggests that there is indeed a role for cellular senescence in shaping the immune response to persistent infection.

EBV-specific CD8+ T cell memory: relationships between epitope specificity, cell phenotype, and immediate effector function.

EBV infection in humans induces CD8+ T cell memory to viral epitopes derived from both lytic and latent cycle Ags. We have analyzed the relationship between the phenotype and function of the memory pool of T cells specific for these Ags. Lytic epitope-specific populations were heterogeneous in terms of CD45RO/RA and CD28 expression, whereas latent epitope-specific populations were uniformly CD45RO+ and CD28+, consistent with the higher antigenic challenge from lytic epitopes driving some memory cells toward a CD45RA+, CD28- phenotype. However, both types of memory population showed immediate epitope-specific cytotoxicity and type 1 cytokine production in ex vivo assays. Cytotoxic function was not associated with preactivated T cells, as EBV-specific populations were negative for activation markers such as CD69 or CD38, nor could cytotoxic function be ascribed to CD27- or CD56+ subsets, as such cells were not detected in EBV-specific memory. Furthermore, cytotoxicity was not limited to CD45RA+ and/or CD28- fractions, but also was observed in CD45RO+, CD28+ populations in lytic and latent epitope-specific memory. Cytokine (IFN-gamma, TNF-alpha) responses, measured by intracytoplasmic staining after peptide stimulation, also were detectable in CD45RO+ and RA+ subsets as well as CD28+ and CD28- subsets. Of other markers that were heterogeneous in both lytic and latent epitope populations, CCR7 gave the best discrimination of functionality; thus, CCR7+ cells consistently failed to give an IFN-gamma or TNF-alpha response, whereas many CCR7- cells were responsive. Our data are consistent with effector functions having a broad distribution among phenotypically distinct subsets of "effector memory" cells that have lost the CCR7 marker.

Serological HLA class I alleles in Senegalese blood donors detected HBs Ag positive.

We analysed the HLA class I alleles in 96 blood donors HBs Ag positive compared with 93 healthy control individuals (HBs negative). The most frequent HLA-A, -B, -C alleles found were, A23 (33.6%); A2 (25%); A30 (25%); B8 (31.5%); B7 (16.3%); B58 (11.9%); B35 (11.9%); B49 (11.9%); B53 (10.8%); Cw7 (39.1%); Cw3 (36.9%); Cw4 (36.9%). Significant differences (P<0.001) were found between the blood donors and the controls for the following HLA alleles, A1; A23; B8 and Cw3. The detection of HBe antigen was positive in 26/84 blood donors. It was observed a significant difference (P<0.01; odds ratios (OR)=6.25) between positive and negative HBe antigens blood donors for HLA-A1 allele.

Allograft loss in renal transplant recipients with Fabry's disease and activated protein C resistance.

INTRODUCTION: Fabry's disease is associated with an increased incidence of thrombotic events and rejection. Spontaneous thrombosis of a functioning cadaveric renal allograft in a recipient with Fabry's disease prompted prospective evaluation of all transplant candidates with Fabry's disease for hypercoagulability. MATERIALS AND METHODS: Transplant candidates with Fabry's disease were tested for hypercoagulability, analyzed for HLA-type and ABO group, and comorbid conditions suggestive of hypercoagulability. RESULTS: A unique association of Fabry's disease with activated protein C Resistance was documented in a cohort of Caucasian male renal transplant recipients with Fabry's disease. Four of five patients were blood group A and had no significant comorbid conditions suggestive of hypercoagulability. The resistance to activation of protein C (APCR)(+) patients shared HLA loci-B8 and Dr3, although the APCR(-) patients shared HLA loci-B27 and -B38. CONCLUSIONS: Due to the observed increase in the incidence of APCR in our Fabry's cohort, we suggest screening all patients with Fabry's disease for APCR. Because factor V and factor Va receptors are found on vascular endothelium and peripheral blood monocytes, APCR in the presence of Fabry's disease may be a nonimmunological stimulus for rejection. Analysis of HLA typing in patients with Fabry's disease may further elucidate HLA-based association of Fabry's disease and resistance to activated protein C with the risk of thrombosis and rejection.

Pattern of human leukocyte antigens in Turkish children with celiac disease.

BACKGROUND: Regional variations in the human leukocyte antigen (HLA) distribution patterns of celiac disease (CD) have been reported. The aim of the present study was to assess the distribution of HLA class I and class II in Turkish children with CD and to compare the findings with a control group. METHODS: Human leukocyte antigen typing was performed in 33 children with CD and in 77 healthy individuals, who served as controls, by using standard National Institutes of Health lymphocytotoxicity techniques. RESULTS: A positive association was found between HLA A2 (42 vs 19% for sick subjects compared with healthy controls, respectively), B8 (39 vs. 9% for sick subjects compared with healthy controls, respectively), CW7 (45 vs. 25% for sick subjects compared with healthy controls, respectively), DR3 (70 vs. 17% for sick subjects compared with healthy controls, respectively), DR7 (30 vs. 13% for sick subjects compared with healthy controls, respectively) and DQ2 (52 vs. 34% for sick subjects compared with healthy controls, respectively). The combinations of DR3-DQ2 (30 vs. 12% for sick subjects compared with healthy controls, respectively), DR3-DR4 (21 vs. 1% for sick subjects compared with healthy controls, respectively) and DR7-DQ2 (21 vs. 6% for sick subjects compared with healthy controls, respectively) were also found to be significantly important in children with CD. The highest relative risk (RR) was for HLA B8 in class I (RR 6.50), for DR3 (RR 11.30) in class II and for combination of DR3-DR4 (RR 20.46). The highest etiologic fraction (EF) was for the DR3 antigen (EF 0.55). CONCLUSIONS: The present study emphasizes that HLA genotypes are an important background to CD development, but some additional susceptibility factors remain to be identified.

Association of tumor necrosis factor polymorphism with primary sclerosing cholangitis.

BACKGROUND/AIMS: Primary sclerosing cholangitis is associated with the HLA haplotypes A1-B8-DRB3*0101-DRB1*0301-DQA1*0501-DQB1*0201 and DRB3*0101-DRB1*1301-DQA1*0103-DQB1* 0603. However, the interpretation of these genetic associations is controversial. One explanation may be that HLA-encoded susceptibility is due to other genes carried on these haplotypes such as the HLA class III tumor necrosis factor genes. The aim of the study was to investigate tumor necrosis factor genetics in a large series of well-defined patients. METHODS: One hundred and ten HLA genotyped patients and 126 control subjects were studied by polymerase chain reaction genotyping for 3 different tumor necrosis factor gene polymorphisms: -308, -238 and an Ncol restriction fragment length polymorphism in the lymphotoxin alpha gene. RESULTS: Overall, 58% of patients had the TNF2 allele, compared with 29% of controls, p(c) = 0.0001. No association was found with either of the other tumor necrosis factor polymorphisms examined. TNF2 was significantly increased in the presence of B8 and DRB3*0101 only, and was independent of DRB1*0301 (p(c)<0.04). The associations with B8 and TNF2 were stronger than the associations with any of the HLA class II alleles examined. CONCLUSION: HLA-encoded genetic susceptibility to primary sclerosing cholangitis may be determined by polymorphism within the HLA class III region, in particular with the TNF2 allele.

The impact of HLA on long-term outcome after thymectomy for myasthenia gravis.

In a retrospective series of 86 patients with myasthenia gravis, the only factors predictive of improvement in muscular strength after transsternal thymectomy were preoperative severity of myasthenia (90% versus 54%, p = 0.0014) and HLA-B8 (79% versus 50%, p = 0.0060) in bivariable and multivariable analyses. Both factors were not interrelated (p = 0.824). The statistical effect of HLA-B8 was independent from preoperative severity of disease. Typing for HLA-B8 may thus be a valuable adjunct in predicting the benefit of thymectomy in myasthenia. The observation that an MHC class I allele is associated with clinical improvement after thymectomy suggests that the clinical course of myasthenia may be influenced by class I restricted T-cells.

Defective expression of CD95 (FAS/APO-1) molecule suggests apoptosis impairment of T and B cells in HLA-B8, DR3-positive individuals.

Activation-induced apoptosis is one of the primary control mechanisms for the negative selection of an immune response, leading to maintenance of immune homeostasis and selective T cell deletion. The interaction between the surface molecule Fas and its ligand (FasL) has been proposed as a primary mechanism initiating T cell apoptosis. The T cell receptor modulates the expression and function of these molecules. Defects in the Fas/FasL apoptosis pathway have been shown to result in autoimmune disease in humans and in murine models. Because subjects carrying the HLA-B8, DR3 haplotype show a number of immune dysfunctions, including membrano-proliferative glomerulonephritis, systemic lupus erythematosus, Graves' disease, and others, we investigated Fas expression on T and B cells, and sensitivity to Fas-mediated apoptosis of activated T cells, to determine whether abnormalities of the Fas pathway might be associated with the development of autoimmune diseases in this group of individuals. Our findings show that B cells and resting T cells from HLA-B8+, DR3+ subjects express markedly reduced levels of Fas compared with those isolated from HLA-B8-, DR3+ individuals. Reduced levels of Fas were also evident on the surface of T cells from HLA-B8+, DR3+ subjects activated in vitro by stimulation with OKT3 and phytohemoagglutinin. Cycling T cells from these subjects, evaluated for apoptotic nuclei by flow cytometry after incubation with a cytolytic anti-Fas mAb, showed a significantly lower percentage of Fas-mediated apoptosis than did those from HLA-B8-, DR3- individuals. Normal levels of apoptosis were restored after exposure to a synthetic ceramide analog (C2). Further elucidation of the interaction of these molecules in autoimmune diseases may lead to better understanding of the pathogenesis of these disorders.

HLA phenotypes in healthy aged subjects.

One hundred and seventy-one unrelated elderly healthy subjects selected according to the Senieur protocol (57 men and 114 women), aged 75-104 years, and 405 healthy individuals (238 men and 167 women), aged 18-65 years, were typed for HLA-A, HLA-B, and HLA-DR antigens. The purpose of the study was to investigate a possible association between HLA antigens and longevity. In the total group of elderly, an increased frequency of HLA-B16 (11.11 vs. 5.43%) and HLA-DR7 (38.33 vs. 15.67%) and a decreased frequency of HLA-B15 (1.75 vs. 5.18%) and HLA-DR4 (11.66 vs. 24.15%) were observed. The HLA-B15DR4 haplotype was not represented (vs. 2.1%), HLA-A1B8 was found with a low frequency (2.9 vs. 4.4%), and HLA-B8DR3 was very rarely found (1.6 vs. 10.1%), whereas the HLA-B13DR7 haplotype was observed with an increased frequency (6.6 vs. 3.3%). These results are in agreement with other published data and suggest that longevity in humans may be influenced by the genetic background.

Clinical heterogeneity of seronegative myasthenia gravis.

We studied 38 patients affected by seronegative myasthenia gravis (SNMG) with age at the onset of the disease ranging from 6 to 66 yr. Clinical follow-up lasted at least 2 yr. Patients' lymphocyte cultures showed in no case anti-acetylcholine receptor antibody production; HLA associations did not differ significantly from those in seropositive MG. In most cases (33 out of 38) the disease differed from seropositive MG only in the low incidence of thymic pathology. In five cases the clinical picture was characterized by prevalent involvement of ocular and bulbar muscles and by a more stable course. These last group of patients did not respond satisfactorily to immunosuppressants, but they clearly improved with plasma-exchange. Mice injected with plasma IgG from four patients (two with typical clinical picture and two with prevalent oculobulbar involvement) showed a defect of neuromuscular transmission. In our experience, SNMG is a heterogeneous disease. A humorally mediated pathogenesis appears to be operating in both groups of patients we described.

HLA antigens and asthma in Greeks.

HLA-A and -B antigens were determined in a group of 76 Greek asthmatic patients: 35 children (1.5-15 years) and 41 adults (18-73 years). The results were compared to those of 400 healthy unrelated controls from the same population. The standard NIH lymphocytotoxicity test was applied. When all 76 patients were compared to the controls, a statistically significant lower frequency of HLA-B5 and -B35 antigens was noted. When adults were analysed alone, an increased frequency of HLA-B8 was found. On the other hand, in the asthmatic children sub-group, the HLA-A10 antigen was significantly higher and the HLA-B5 was significantly lower than in the controls. These data imply that different HLA antigens may be involved in the pathogenesis of several clinical forms of asthma and that, in order to study the role of immunogenetic factor(s) in the pathogenesis of this disease, more adequate grouping criteria are needed.

Association of HLA types A1-B8-DR3 and B27 with rapid and slow progression of HIV disease.

We examined how HLA types A1-B8-DR3 and B27 were related to progression of clinical disease and rate of loss of CD4 lymphocytes in the Edinburgh City Hospital cohort of HIV-positive patients, mainly injection drug users. Patients (n = 692) were prospectively followed from 1985 through March 1994. Accurately estimated seroconversion times were determined retrospectively for a subgroup of 313 (45%). Of 262 patients (39%) who were fully or partially HLA typed, 155 (50%) had known seroconversions. Of 34 patients typed positive for A1-B8-DR3, 29 progressed to CDC stage IV, 22 to AIDS and 20 died. Twelve patients were typed positive for B27; six of these progressed to CDC stage IV, one to AIDS and none died. In a proportional hazards analysis of the 313 patients with known seroconversions, A1-B8-DR3 was significantly associated with covariate-adjusted relative risks of 3.7 (95% CI 1.9-7.2), 3.1 (1.6-6.0) and 1.9 (1.1-3.2) for progression from seroconversion to death, AIDS and CDC stage IV, respectively. Events for B27 were too rare to include B27 in analyses to death and AIDS, but B27 was significantly associated with slower progression to CDC stage IV (0.3, CI 0.1-0.9). Random effects growth curve models were used to estimate individual rates of loss of square root CD4 count and loss of CD4 percentage, for 603 and 617 patients, respectively. A1-B8-DR3 was associated with rapid loss of both markers (p = 0.02 and p = 0.01, respectively); B27 was associated with slow loss of both markers (p = 0.04 and p < 0.005).

Immunologic features and HLA associations in chronic viral hepatitis.

BACKGROUND/AIMS: Chronic viral hepatitis may have immunologic manifestations, and such features may reflect genetic predispositions. The aim of this study was to assess associations between immune manifestations and HLA-DR antigens. METHODS: Ninety-five patients were evaluated prospectively for immunologic features. A microlymphocytotoxicity technique was used to determine DR3, DR4, and A1-B8-DR3 phenotypes. DR antigens were also determined by restriction fragment length polymorphism in 76 patients with chronic viral hepatitis and 80 normal subjects. RESULTS: Autoantibodies were found in 59 patients (62%), and concurrent immunologic diseases were found in 22 patients (23%). Patients with antinuclear antibodies had the A1-B8-DR3 phenotype more commonly than seronegative counterparts (26% vs. 6%; P = 0.02) and had DR3 positivity more frequently than normal subjects (41% vs. 18%; P = 0.03). In contrast, patients with concurrent immunologic diseases had DR4 positivity more commonly than patients without these findings (68% vs. 27%; P = 0.001) and normal subjects (68% vs. 30%; P = 0.003). CONCLUSIONS: Patients with chronic viral hepatitis commonly have autoantibodies and/or concurrent immunologic diseases. The expression of antinuclear antibodies is associated with the A1-B8-DR3 phenotype, and the presence of concurrent immunologic diseases is associated with the DR4 phenotype. In these instances, autoimmune expression may reflect a genetic predisposition that is facilitated by viral infection or is coincidental with it.

[Familial sarcoidosis: 3 cases in the same family]. / Sarcoïdose familiale: trois cas dans la même fratrie.

Familial sarcoidosis is uncommon, representing less than 5% of the cases. We reported three cases of sarcoidosis in the same family (two sisters and a brother) with different clinical presentation in spite of the presence in each patient of HLA B8 DR3. These HLA phenotype may be related with favourable sarcoidosis. Until the two sisters had articular and benign lymph nodes diseases, the brother had multivisceral sarcoidosis involving the liver, the lung and the mediastinum. Corticosteroid were used during 6 month with favourable evolution. There is 16 years between the three sarcoidosis history but the disease appeared till the third decade. The two sisters and the brother did not live in the same city. These suggest than genetic predisposition is more effective than environmental basis.