HLA class I and class II antigens in sarcoidosis.

BACKGROUND: Sarcoidosis is a multisystem granulomatous disorder. Its exact cause is unknown, but it is believed that an external agent may cause the characteristic immune reaction in genetically susceptible individuals. There is therefore general recognition that genetic vulnerability to sarcoidosis is one of the potential risk factors. HLA is encoded by genes in the major histocompatibility complex on chromosome 6. These surface cells are important in presentation of antigen and play a key part in the body's immune response to external antigens. Various HLA subtypes are more common in people with sarcoidosis than in those without. Variances in vulnerability, presentation, progression and prognosis have been related to different HLA phenotypes. HLA genes offer information into the factors driving sarcoidosis and prognosticating tools. However, in Africa, including South Africa (SA), there are no data on HLA types in relation to sarcoidosis. OBJECTIVES: To determine HLA class I and II associations in SA sarcoidosis patients. METHODS: Phenotype frequencies of HLA-A, B and C and DQB1 and DRB1 were calculated for 51 consecutive patients with biopsy-proven sarcoidosis attending the respiratory clinic at Charlotte Maxeke Johannesburg Academic Hospital and 63 controls, who were potential organ donors. The frequencies of the tested HLA loci were determined by direct counting. The significance of the associations between the various loci tested for and the presence or absence of sarcoidosis was estimated from 2 × 2 tables using the χ2 test. RESULTS: Of the 51 patients, 70.6% were female. The mean age was 44.6 years. Analysis of HLA class I and class II phenotypes in sarcoidosis patients revealed a significant association with HLA-B15, C4, C7, C12, C15, C16, C17, DQ3, DR8 and DR11. In addition, a significant negative (protective) association with HLA A9, A28, B12, B17 and DR2 was observed. CONCLUSION: This HLA study in SA patients suggests that genetic factors play a role in the causation of sarcoidosis. Some HLA subtypes have a significant association with sarcoidosis in SA patients, while other subtypes may be protective. The study supported the association of HLA antigens with sarcoidosis and implies that there is a genetic predisposition to sarcoidosis in the SA population.

HLA class I and class II antigens in sarcoidosis

Background. Sarcoidosis is a multisystem granulomatous disorder. Its exact cause is unknown, but it is believed that an external agent may cause the characteristic immune reaction in genetically susceptible individuals. There is therefore general recognition that genetic vulnerability to sarcoidosis is one of the potential risk factors. HLA is encoded by genes in the major histocompatibility complex on chromosome 6. These surface cells are important in presentation of antigen and play a key part in the body's immune response to external antigens. Various HLA subtypes are more common in people with sarcoidosis than in those without. Variances in vulnerability, presentation, progression and prognosis have been related to different HLA phenotypes. HLA genes offer information into the factors driving sarcoidosis and prognosticating tools. However, in Africa, including South Africa (SA), there are no data on HLA types in relation to sarcoidosis.Objectives. To determine HLA class I and II associations in SA sarcoidosis patients.Methods. Phenotype frequencies of HLA-A, B and C and DQB1 and DRB1 were calculated for 51 consecutive patients with biopsy-proven sarcoidosis attending the respiratory clinic at Charlotte Maxeke Johannesburg Academic Hospital and 63 controls, who were potential organ donors. The frequencies of the tested HLA loci were determined by direct counting. The significance of the associations between the various loci tested for and the presence or absence of sarcoidosis was estimated from 2 × 2 tables using the χ2 test.Results. Of the 51 patients, 70.6% were female. The mean age was 44.6 years. Analysis of HLA class I and class II phenotypes in sarcoidosis patients revealed a significant association with HLA-B15, C4, C7, C12, C15, C16, C17, DQ3, DR8 and DR11. In addition, a significant negative (protective) association with HLA A9, A28, B12, B17 and DR2 was observed.Conclusion. This HLA study in SA patients suggests that genetic factors play a role in the causation of sarcoidosis. Some HLA subtypes have a significant association with sarcoidosis in SA patients, while other subtypes may be protective. The study supported the association of HLA antigens with sarcoidosis and implies that there is a genetic predisposition to sarcoidosis in the SA population.

Clinical and serological correlates of antinucleosome antibodies in South Africans with systemic lupus erythematosus.

Antinucleosome antibodies (AnuA) are increasingly recognized as an important biomarker in the diagnosis and subset stratification of patients with systemic lupus erythematosus (SLE). The aim of the study was to determine the sensitivity, specificity, and clinico-serological correlates of AnuA in black South Africans with SLE. We performed a cross-sectional study of 86 SLE patients attending a tertiary center and 87 control subjects. AnuA were tested using a second-generation enzyme-linked immunosorbent assay (ELISA). The sensitivity, specificity, positive predictive value, and negative predictive value of AnuA were 45.3, 94.3, 88.6, and 63.6%, respectively. The presence of AnuA were strongly associated with the co-presence of anti-dsDNA antibodies (OR = 3.4, p < 0.0005) and antihistone antibodies (OR = 15.7, p < 0.00001). Patients who were seropositive for AnuA were more likely to have skin involvement (discoid lupus and/or malar rash) and had higher SLE disease activity index (SLEDAI) scores and Systemic Lupus International Collaborative Clinics/American College of Rheumatology (SLICC/ACR) damage scores (p < 0.05). IgG anticardiolipin antibody (aCL) levels showed a significant correlation with AnuA ratios (p < 0.01). Our findings provide further evidence that AnuA are a sensitive and specific diagnostic biomarker in SLE. Moreover, our finding that the presence of AnuA, but not anti-dsDNA antibodies, are associated with worse SLICC/ACR damage scores suggest that AnuA may have a role in predicting disease outcome. The correlation between IgG aCL and AnuA is a novel finding that merits further studies to determine possible common peptide specificities of the antibodies.

Immunoglobulin responses to a repeated bout of downhill running.

OBJECTIVE: To examine the effect of downhill running on immunoglobulin responses. METHOD: Eleven untrained men performed 2 x 60 minute bouts of downhill running (-13.5% gradient), at a speed eliciting 75% of their vO2peak on a level grade. Two runs were spaced 14 days apart. Serum samples were collected before, after, and every hour for 12 hours and every 24 hours for six days. Serum total creatine kinase and immunoglobulin isotypes and subclasses were measured, and results were analysed using a repeated measures analysis of variance (12 hour period, 2 x 14; 24 hour intervals, 2 x 6, p < or = 0.05). RESULTS: There was a significant interaction effect for creatine kinase (activity lower after run 2 than after run 1, 6-24 h) and exercise effect, with the serum concentrations of IgG1, IgG2, IgG4, and IgE lower, and IgM higher, after run 2. CONCLUSION: Lower concentrations of IgG1, IgG2, and IgE after run 2 may reflect a dampened autoimmune inflammatory response to autoantigens and enhanced autoantigen clearance mediated by the upregulation of IgM.

Changes in mucosal and humoral atopic-related markers and immunoglobulins in elite cyclists participating in the Vuelta a España.

Atopic-related factors, humoral and mucosal immunoglobulins (Ig), and cortisol were measured in 17 professional cyclists competing in the 2003 Vuelta a España (a three-week multi-stage race). Venous blood and saliva samples were obtained the morning before the start of the race (T0), on the first rest day after 10 days of racing (T1), and before the start of the last stage after 21 days of racing (T2). Atopic-related factors, IgE, eosinophil cationic protein (ECP), and eosinophils, were significantly altered during the race. Serum IgE (T1: + 10 %) and ECP (salivary, T1: 113 % and serum, T2: 155 %) were significantly increased, while eosinophils (T1: - 32 %, T2: - 55 %) were significantly lower, than pre-race levels. Salivary sIgA secretion rate was significantly decreased at T2 (- 36 %). Pearson product-moment correlations revealed a modest correlation between salivary sIgA and salivary ECP (T1: r = 0.30; T2: r = 0.48; p < 0.01). Serum IgM, total IgG, IgG1, IgG2, IgA levels, at T1 and T2, and cortisol at T2, were significantly lower than pre-race levels. In conclusion, the elevation in IgE and ECP suggests an up-regulation of atopic-related factors in professional cyclists participating in the Vuelta a España. The correlation between salivary sIgA and salivary ECP indicates a role for sIgA in mediating mucosal inflammation. The alterations in Ig levels may indicate Ig isotype switching. An increasing state of hormonal fatigue may have influenced the observed immune alterations.

Serum concentrations of C reactive protein, alpha1 antitrypsin, and complement (C3, C4, C1 esterase inhibitor) before and during the Vuelta a Espana.

OBJECTIVES: To determine serum concentrations of proinflammatory (C reactive protein, complement C3 and C4) and anti-inflammatory (alpha(1) antitrypsin, C1 esterase inhibitor (C1-INH)) acute phase proteins in elite cyclists before and during a three week cycle tour. METHODS: Seventeen professional cyclists participating in the Vuelta a Espana volunteered for the study. Their mean (SD) physical characteristics were: age 28 (1) years; height 1.7 (0.06) m; weight 65 (7) kg; body fat 7.6 (0.8)%; Vo(2)max 75.3 (2.3) ml/kg/min. Venepuncture was performed on each subject 24 hours before the tour began (T0), on day 11 (the first rest day; T1) and day 21 (the second to last stage of the tour; T2). Samples at T1 and T2 were taken about 17 hours after the previous stage. Analysis of variance was used to determine changes over time. Where significance was found, a Tukey post hoc test was performed. RESULTS: C reactive protein concentrations were consistently within the normal range, although there was a 228%, non-significant increase at T1. C3 concentrations fell within the normal range at all times assessed. C4 concentrations before the race were within the normal range and were significantly increased 10 days (T1) into the race. C1-INH concentrations did not change significantly throughout the race. alpha(1) Antitrypsin concentration before the race was at the lower end of the normal range and was only significantly raised at T2. CONCLUSIONS: Although not as pronounced as those reported in marathon/ultramarathon runners, elite cyclists participating in a three week cycle tour experienced increases in selected proinflammatory and anti-inflammatory acute phase proteins, indicating an acute phase/inflammatory response. It is tenable that the increase in alpha(1) antitrypsin and C1-INH (anti-inflammatory mediators) at T2 served to attenuate the acute phase/inflammatory response. The lower than normal resting concentrations of the acute phase proteins supports the notion that chronic aerobic exercise induces an anti-inflammatory state.

Influence of ultra-endurance exercise on immunoglobulin isotypes and subclasses.

BACKGROUND: Strenuous exercise is associated with tissue damage. This activates the innate immune system and local inflammation. Interaction between innate and adaptive immunity is essential for maintaining health, suggesting that the adaptive immune system may also be altered by exercise. OBJECTIVES: To determine exercise induced changes in the adaptive immune system by measuring the immunoglobulin isotype and subclass response to an ultra-marathon. METHODS: Venepuncture was performed on 11 experienced volunteers (six men, five women; mean (SD) age 43 (9.8) years) 24 hours before the projected finishing time and immediately after and 3, 24, and 72 hours after an ultra-marathon (90 km). Serum was stored at -80 degrees C. IgM, IgD, IgA, IgG, IgG1, 2, 3, and 4, and total IgE were measured. RESULTS: The following immunoglobulins were significantly (p< or =0.05) altered after the race: IgD, immediately (-51%) and 24 hours (-41%) after; IgM 24 hours after (-23%); total IgG immediately after (+12%). There were no reports of symptoms of upper respiratory tract infections after the ultra-marathon. CONCLUSIONS: In experienced ultra-endurance runners, alterations in immunoglobulin concentrations after a race suggest an enhanced immune response, including isotype switching, interactions with the innate immune system, and a secondary antibody response. These alterations may have a role in the maintenance of subject health after an ultra-marathon.

HLA class I and class II antigens associated with multiple myeloma in southern Africa.

While the exact aetiology of myeloma is unknown, genetic factors feature among the potential risk factors. The HLA phenotypes in African blacks with myeloma (the commonest haematopoietic malignancy in this group) have not been characterized. The purpose of this study was to determine the HLA class I and class II phenotypes of patients with multiple myeloma and to compare the findings to an ethnically matched control group of 100 individuals. Analysis of the HLA class I and class II phenotypes in 62 myeloma patients revealed: (i) a corresponding statistically significant association with HLA B18 [odds ratio (OR) 6.3; 95% confidence interval (CI) 1.013-39.727; P < 0.005]; (ii) no statistically significant association with HLA B13, Cw2, Cw6 or the DR and DQ antigens; and (iii) a statistically significant negative (protective) association with HLA Cw7 (OR 0.4; 95% CI 0.21-0.87; P < 0.005). This study suggests that although genetic factors may play a role in the multifactorial aetiology of multiple myeloma, with the exception of HLA B18, there is no specific association between HLA types and multiple myeloma in South African blacks.

In the rationing of healthcare in indigent African populations, which services should come first?

Governments, worldwide, have enormous difficulties in affording adequate funds for healthcare and its maintenance. In developing populations, almost all of whom are indigent, the diverse health problems being faced with limited funds are insufficiently appreciated. Information is given, for both developed and developing populations, principally those in sub-Saharan Africa, regarding various countries' gross national product (GNP) per capita, the percentage of GNP devoted to health services, and the allocation of health funds per capita. To illustrate the formidable health problems prevailing, some data are given on the magnitudes of morbidity/mortality situations, both for communicable and non-communicable diseases. Some examples are provided which exemplify opposing points of view regarding strongly contesting health claims for priorities in monetary support. Additionally, examples are given of some impoverished countries, which, despite highly adverse circumstances, have achieved enviable health statistics. In this respect it would be highly beneficial were the circumstances and means employed in these and similar contexts given wide publicity.

Acute phase proteins in major depression.

Extensive evidence exists associating depression with changes in the immune system. The present study evaluates the levels of complement components C3 and C4, C-reactive proteins, and IL-6 in patients who met DSM-III-R diagnostic criteria for major depressive disorder, as well as controls. Whereas no significant differences between the mean levels of C3 could be detected between depressed patients and controls, the levels of C4, IL-6 (where detected), and C-reactive protein were significantly raised in the group with a depressive disorder. Our study suggests an interaction between psychological state and immune systems operative in host defenses.

An evaluation of the capillus HIV-1/HIV-2 latex agglutination test using serum and whole blood.

The capillus HIV-1/HIV-2 latex agglutination (LA) test was evaluated for its potential as an initial screening test in primary health care. For the serum study, panels totalling 289 HIV-positive sera and 323 known HIV-negative sera plus 50 individual seroconversion samples were tested by capillus. Paired blood specimens were also collected in heparinized and plain tubes from 501 consecutive patients with newly diagnosed sexually transmitted diseases (STDs) attending an STD clinic at a Transvaal hospital. Overall, an initial sensitivity of 99.3% and an initial specificity of 99.7% were obtained by visual reading of the capillus HIV-1/ HIV-2 LA tests on serum samples. Capillus also detected 40 (80%) of the 50 seroconversion samples. Of the 501 paired plain and heparinized blood specimens, serum testing by enzyme immunoassay (EIA) and indirect immunofluorescence/ Western blot (IFA/WB) showed 147 (29%) to be HIV Ab positive. Capillus testing of the paired specimens correctly identified all 147 known positive patients and 345 of the 346 negative patients, thus showing an initial sensitivity of 100% and an initial specificity of 99.7% for the testing of heparinized whole blood by a relatively unskilled health worker. It was concluded that the capillus HIV-1/HIV-2 LA test would be suitable for use as a primary screening test in small outlying laboratories or primary health care clinics.

The pro-oxidative riminophenazine B669 neutralizes the inhibitory effects of Mycobacterium tuberculosis on phagocyte antimicrobial activity.

The effects of clofazimine, a riminophenazine antimicrobial agent, and its analogue B669 on phagocyte functions have been investigated. Clofazimine, at concentrations attainable in vivo, and B669, in particular, increased the intracellular killing ability of phagocytes following appropriate cell stimulation. Similarly, nitro blue tetrazolium reduction, hydrogen peroxide production, lysosyme release and hexose monophosphate shunt activity were all increased by treating phagocytes with the riminophenazines. It has previously been shown that a 25 kDa glycolipoprotein derived from Mycobacterium tuberculosis inhibits phagocyte functions associated with phagocyte antimicrobial activity. The present study confirms these observations. A further aspect of the study examined the ability of riminophenazines to reverse the inhibition of phagocyte functions by the 25 kDa mycobacterial fraction. Whilst both riminophenazines were capable of partially but significantly reversing the inhibition due to the mycobacterial fraction, the restorative capacity of B669 was greater than that of clofazimine.

The inhibitory effects of Mycobacterium tuberculosis on MHC class II expression by monocytes activated with riminophenazines and phagocyte stimulants.

The expression of MHC class II antigens by peripheral blood monocytes from normal individuals was investigated. Class II expression as determined by a cell ELISA was effectively induced by various phagocyte stimulants. A further aspect of our study investigated the effects of clofazimine, a riminophenazine antimicrobial agent and its analogue, B669, on class II expression. Both agents at concentrations attainable in vivo increased the expression of MHC class II antigens. A 25-kD glycolipoprotein derived from Mycobacterium tuberculosis that inhibits phagocyte functions has previously been described. This component significantly reduced the expression of MHC class II antigens induced by the riminophenazines, clofazimine and B669, interferon-gamma (IFN-gamma) or opsonised yeast when added at the initiation of experiments. The riminophenazines could not restore the decrease in class II antigen expression previously inhibited by the 25-kD mycobacterial fraction. However, cultures prestimulated with the riminophenazines or phagocyte stimulants were unaffected by the 25-kD mycobacterial fraction. The results suggest the potential use of these agents as modulators of phagocyte function.

HLA expression in hepatocellular carcinoma cell lines.

The present study undertook to investigate the biological significance of human leucocyte antigen expression in hepatocellular carcinoma and to elucidate the role of potential modulating agents on human leucocyte antigen expression. These studies used several hepatic tumour-derived cell lines as in vitro model systems. The cell lines included PLC/PRF/5 (Alexander cell line), Hep3B, HepG2, TONG PHC, HA22T/VGH, HA59T/VGH and Mahlavu. The cell lines K562 and Raji were used as negative and positive controls, respectively. K562, a B lymphoid-derived cell line, was shown to express negligible amounts of human leucocyte antigens, while Raji, an erythromyeloid-derived cell line, expressed both class I and class II human leucocyte antigens as well as their respective invariant chains, beta 2-microglobulin and Ii. Using an ELISA, experiments performed on these cell lines confirmed the natural expression of class I and class II antigens by the HA22T/VGH and HA59T/VGH cell lines, whereas PLC/PRF/5 displayed class II surface antigens only. The effects of modulating agents such as interferon-gamma sodium butyrate and clofazimine on human leucocyte antigen expression were investigated using the HA22T/VGH, HA59T/VGH and TONG PHC cell lines. These agents increased class II and class II human leucocyte antigen expression on HA22T/VGH and TONG PHC cells, but had no effect on the HA59T/VGH cell line. The results suggest a potential use for these agents as modulators of human leucocyte antigen expression by human heptocellular cell lines.