Major histocompatibility complex (MHC) class III genetics in two Amerindian tribes from southern Brazil: the Kaingang and the Guarani.

Population genetic studies of the major histocompatibility complex (MHC) class III region, comprising C2, BF and C4 phenotypes, and molecular genetic data are rarely available for populations other than Caucasoids. We have investigated three Amerindian populations from Southern Brazil: 131 Kaingang from Ivaí (KIV), 111 Kaingang (KRC) and 100 Guarani (GRC) from Rio das Cobras. Extended MHC haplotypes were derived after standard C2, BF, C4 phenotyping and restriction fragment length polymorphism (RFLP) analysis with TaqI, together with HLA data published previously by segregation analysis. C2 and BF frequencies corresponded to other Amerindian populations. C4B*Q0 frequency was high in the GRC (0.429) but low in the Kaingang. Unusual C4 alleles were found, viz. C4A*58, A*55 and C4B*22 (presumably non-Amerindian) and aberrant C4A*3 of Amerindian origin occurring with a frequency of 0.223 in the GRC. C4A*3 bands of homo- and heterozygous individuals carrying this variant were Rodgers 1 positive and Chido 1,3 positive, showed a C4A specific lysis type and a C4A like alpha-chain. Polymerase chain reaction studies and sequencing showed that this is based on a C4A*3 duplication with a regular C4A*3 and a partially converted C4A*0304 carrying the C4B specific epitopes Ch 6 and Ch 1,3. Associations of class III haplotypes with particular RFLP patterns were similar to those reported for Caucasoids. The previously described association between combined C4A and CYP21P deletions and the 6.4 kb TaqI fragment was not seen in these Amerindians. This fragment occurred within a regular two locus gene structure in the Kaingang, representing a "short" gene at C4 locus I. C4 and CYP21 duplications were frequently observed. The distribution of extended MHC haplotypes provides evidence for a close relationship between the KIV and KRC and a larger genetic distance between the two Kaingang groups and the GRC.

Clinical, autoimmune and demographic profile in systemic lupus erythematosus (SLE) patients from southern Brazil.

With the purpose of determining the association of clinical, autoimmune and demographic features, a group of 90 SLE patients from Southern Brazil were investigated. At diagnosis, 24% of them were under 20 years, 63% were between 20 and 40 years and 13% were older than 40 years. According to the ethnic background, there were 66% Brazilian-white patients, 21% Caucasians and 13% Mullatos/Blacks. Antinuclear antibodies (ANA) were present in 98%, anti-ds-DNA in 56% and anti-Sm in 31% of the patients. Anti-ds-DNA were more prevalent in the Caucasians (79%), while anti-Sm were increased in the Mullatos/Blacks (58%, p < 0.02) as compared to the white patients (Brazilian-whites = 22% and Caucasians = 42%). Neurologic involvement had lower prevalence in the group of Mullato/Black patients (8%) than in the Brazilian-whites (32%) and Caucasians (31%). Serositis was present in 51% of the Brazilian-whites, in 21% of the Caucasians and in 41% of the Mullatos/Blacks. On the other hand, the Mullato/ Black group had an increased prevalence of vasculitis (50%) and none of them presented with Raynaud's phenomenon. Younger patients at diagnosis presented higher frequency of renal involvement (p < 0.05), anti-ds-DNA positivity (p < 0.02) and more severe disease (p < 0.07), and in those patients diagnosed after age 40, 33% presented with Raynaud's phenomenon (p < 0.05). Regarding the anti-ds-DNA positivity, 78% of the patients had renal involvement (p < 0.01 RR 2.2) and 66% severe disease (p < 0.05). These results might be important in assessing clinical subsets and may aid individualized management of Brazilian SLE patients. Also, they may corroborate the need for special attention to racial composition in clinical and immunogenetic studies.

Increased frequency of the C4A*6 rare allele in rheumatic heart disease.

The aim of the present investigation was to determine whether the alleles of the MHC class III complement proteins BF, C2 and C4 (C4A and C4B) could be markers for RHD in the Brazilian population. Forty-nine patients with chronic RHD were studied. The controls included 65 healthy unrelated individuals, matched with the patients according to sex, age and ethnical background. BF, C2, C4A and C4B allotypes were determined by standard technologies including Western blots for C2 and C4 variants with monoclonal and policlonal antibodies. The results showed a significantly elevated presence of the C4A*6 rare allele (p = 0.003 RR = 11.85) and a decrease of C4A*3 in the patients. In addition, C4 null and BF and C4 rare alleles were more frequent in patients than in the controls. Considering that in this investigation only RHD patients were included, further studies are necessary in order to clarify whether C4A6 is a marker for the cardiac form or for the disease itself.

Adherence of monocytes and polymorphonuclear cells to infective larvae of Strongyloides stercoralis after complement activation.

The activation of the complement system by living Strongyloides stercoralis filariform larvae and their antigenic preparation was demonstrated in vitro through both classical and alternative pathways. This activation does not require the presence of specific antibodies but promotes the adhesion of peripheral blood monocytes (MNC) and polymorphonuclear cells (PMNC) to the larval surface. Larvae, totally coated by PMNC, showed a visible loss of motility after 2 hr incubation. Ethylenediamine tetraacetic acid, in contrast to ethylene glycol-bis beta-aminoethylether N,N,N,N-tetraacetic acid, abolished the adherence activity, suggesting the involvement of the alternative pathway in this process. Deposition of complement components C1q, C3, C4, C8, and properdin on the larval surface was demonstrated by immunofluorescence assays. In addition, complement activation by the larvae was demonstrated through C3 conversion and C4 cleavage assays, both depending on the number of larvae. On the other hand, complement activation by S. stercoralis antigen was determined by factor B and C4 cleavage, as well as C3 conversion assays. Our results suggest that the complement system as a first line of defense, in association with the effector cells, plays an important role in the nonspecific immune response of the host to S. stercoralis infection, especially considering the constant parasite recycling through the host tissues.

Association of C4B deficiency (C4B*Q0) with erythema nodosum in leprosy.

A considerable number of studies have postulated significant associations between susceptibility to the different clinical manifestations of leprosy and the MHC. In this investigation, the association between the MHC class III complement proteins C2, BF, C4A and C4B and leprosy in a patient population of Southern Brazil was studied. A total of 109 non-related leprosy patients was investigated; 73 presented with lepromatous leprosy (LL), 46 of them had the immunopathological reaction of erythema nodosum (ENL), the remaining 36 were tuberculoid, borderline and indeterminate leprosy (TIBL) patients. The control group included 172 healthy individuals matched with the patients according to their ethnic and geographical origin. C2, BF, C4A and C4B allotypes were determined by standard technologies including Western blots for C2 and C4 variant alleles with monoclonal and polyclonal antibodies. Non-expressed ('silent') C4 alleles in hemizygously deficient individuals were estimated semiquantitatively on the basis of the C4A and C4B isotype ratio and by the MASC ('minimal chi-square') method. The results showed a significantly elevated presence of the non-expressed C4B allele (C4B*Q0) in the LL and ENL patient groups in comparison with the controls. The most significant difference was observed in the ENL group when compared with the controls. In addition, all patients who were homozygously C4B-deficient had ENL, and most of them had the BF*F1 allele. The comparison between LL patients with and without ENL also showed a statistically significant difference in the presence of C4B*Q0, indicating that C4B deficiency itself is associated with ENL. The relative risk of LL patients with the C4B*Q0 allele suffering from ENL was 5.3 compared with LL patients without C4B*Q0. Since immune complexes (IC) are considered to be the pathogenic cause of ENL, our findings indicate that C4B deficiency may play an important role in the abnormal immune response against Mycobacterium leprae and in the lack of IC clearance, leading to ENL reactions. Individuals with this allele seem to be at a higher risk of developing pathological immune reactivity in lepromatous leprosy.

BF and C3 genetic polymorphisms in Kaingang Indians from southern Brazil.

The distribution of C3 and BF variants was determined in a sample of 239 Kaingang Indians. The corresponding gene frequencies were as follows: BF*S = 0.9393, BF*F = 0.0356, BF*S05 = 0.0251, C3*S = 0.9769, C3*F = 0.0231. The presence of the BF*S05 allele, which has previously been found only in a Brazilian population, suggests that this allele originated in Amerindians. The comparatively low degree of polymorphism with high frequencies of BF*S and C3*S is in accordance with the relatedness of the Kaingang with other Amerindians, Eskimos and Asian populations.

Association of major histocompatibility complex class III complement components C2, BF, and C4 with Brazilian paracoccidioidomycosis.

A genetic influence of the major histocompatibility complex (MHC) on the susceptibility and the development of the different clinical forms of paracoccidioidomycosis (PCM) has been postulated. In the present investigation allotypes of MHC-coded class III gene products (complement components C2, BF, C4A, and B) were determined in 69 Brazilian PCM patients and 225 healthy control individuals matched for ethnic and geographic origin. The frequency of the non-expressed C4B allele (C4B*Q0) was significantly elevated in comparison to the controls (p less than 0.01; Fisher's exact test). Three out of 69 patients had a complete C4B deficiency as against 2 among 223 control individuals. The C4A*Q0 allele was also more frequent in the patients. Other C4 alleles were not seen to differ between the two groups. The analysis of BF allotypes showed a non-significant predominance of the rarer allele BF*S07 in the patients, whereas no difference in the distribution of C2 alleles was seen. The data on MHC class III association may support the hypothesis of immune response modulation in PCM and suggest a functional genetic role of complement action against the fungus and in the outcome of PCM infection. We conclude that MHC class III products, especially C4B*Q0, are associated with chronic uni- or multifocal PCM and may influence the course of the infection.

[Comparative studies on properdin factor B (Bf) polymorphism in random samples from Brazil, Germany and Guinea-Bissau]. / Vergleichende Untersuchungen über den Properdin-Faktor B (Bf)-Polymorphismus an Stichproben aus Brasilien, Deutschland und Guinea-Bissau.

Three different population samples have been tested for properdin factor B markers: 395 individuals from Schleswig-Holstein (Germany), 343 individuals (Europids) from Southern Brazil, and 309 individuals (Negroids) from Guinea-Bissau (Western Africa). These samples are showing marked differences in the distribution of Bf gene frequencies. As for the sample from Southern Brazil the Bf data are confirming the assumption that the Caucasoid population in Southern Brazil is somewhat mixed with Negroids.