Major histocompatibility complex phenotypes influence serum testosterone concentration. (17/379)

OBJECTIVES: (a) To confirm our earlier observation that the phenotype HLA-DR4,7 occurs with higher frequency in male patients with rheumatoid arthritis (RA) than in female patients. (b) To test the hypothesis that DR7 is associated with low normal serum testosterone (Te) levels in healthy males; this might explain the increased frequency of DR4,7 in male patients since there appears to be a relationship between low serum Te and RA. (c) To characterize the association between HLA alleles and serum Te concentration in healthy males. METHODS: An additional 82 Newfoundland (NF) RA patients were HLA-DR typed and, combined with our earlier data and data from the 11th International Histocompatibility Workshop, gave HLA-DR and sex information on 373 RA patients. Ninety-four healthy NF males were typed for HLA, the microsatellite marker TNFa (located close to the tumour necrosis factor alpha gene) and complement factor B (BF). An additional 38 males were included, selected partly based on their HLA-B type. RESULTS: We confirmed our earlier finding of a higher frequency of HLA-DR4,7 in male RA patients compared with female RA patients (P<0.01). Contrary to our expectations we found that DR7 was associated with higher than mean values of Te as were B5, B27, DR1, TNFa7 and BF F positivity. Conversely, low Te concentrations were found in men with B15, DR2, DR5, TNFa5 and who were BF F negative. In 28 male 'early-onset' RA patients we did not find an increased frequency of HLA alleles associated with low Te levels as compared with the frequency in 41 'late-onset' patients, suggesting that if low Te level is a risk factor and is present before onset of RA then the level cannot be explained by an association between Te level and major histocompatibility complex (MHC) phenotype. CONCLUSION: This study indicates that a man's MHC phenotype may influence his serum Te concentration, but the relationship of this, if any, to the pathogenesis of RA remains an area of speculation.  (+info)

Cooperation between decay-accelerating factor and membrane cofactor protein in protecting cells from autologous complement attack. (18/379)

Decay-accelerating factor (DAF or CD55) and membrane cofactor protein (MCP or CD46) function intrinsically in the membranes of self cells to prevent activation of autologous complement on their surfaces. How these two regulatory proteins cooperate on self-cell surfaces to inhibit autologous complement attack is unknown. In this study, a GPI-anchored form of MCP was generated. The ability of this recombinant protein and that of naturally GPI-anchored DAF to incorporate into cell membranes then was exploited to examine the combined functions of DAF and MCP in regulating complement intermediates assembled from purified alternative pathway components on rabbit erythrocytes. Quantitative studies with complement-coated rabbit erythrocyte intermediates constituted with each protein individually or the two proteins together demonstrated that DAF and MCP synergize the actions of each other in preventing C3b deposition on the cell surface. Further analyses showed that MCP's ability to catalyze the factor I-mediated cleavage of cell-bound C3b is inhibited in the presence of factors B and D and is restored when DAF is incorporated into the cells. Thus, the activities of DAF and MCP, when present together, are greater than the sum of the two proteins individually, and DAF is required for MCP to catalyze the cleavage of cell-bound C3b in the presence of excess factors B and D. These data are relevant to xenotransplantation, pharmacological inhibition of complement in inflammatory diseases, and evasion of tumor cells from humoral immune responses.  (+info)

Attenuation of experimental autoimmune demyelination in complement-deficient mice. (19/379)

The exact mechanisms leading to CNS inflammation and myelin destruction in multiple sclerosis and in its animal model, experimental allergic encephalomyelitis (EAE) remain equivocal. In both multiple sclerosis and EAE, complement activation is thought to play a pivotal role by recruiting inflammatory cells, increasing myelin phagocytosis by macrophages, and exerting direct cytotoxic effects through the deposition of the membrane attack complex on oligodendrocytes. Despite this assumption, attempts to evaluate complement's contribution to autoimmune demyelination in vivo have been limited by the lack of nontoxic and/or nonimmunogenic complement inhibitors. In this report, we used mice deficient in either C3 or factor B to clarify the role of the complement system in an Ab-independent model of EAE. Both types of complement-deficient mice presented with a markedly reduced disease severity. Although induction of EAE led to inflammatory changes in the meninges and perivascular spaces of both wild-type and complement-deficient animals, in both C3(-/-) and factor B(-/-) mice there was little infiltration of the parenchyma by macrophages and T cells. In addition, compared with their wild-type littermates, the CNS of both C3(-/-) and factor B(-/-) mice induced for EAE are protected from demyelination. These results suggest that complement might be a target for the therapeutic treatment of inflammatory demyelinating diseases of the CNS.  (+info)

Activation of the alternative pathway of human complement by haemoglobin. (20/379)

Haemoglobin solutions (concentration greater than 1.5 mg/ml), prepared from lysates of erythrocytes from a normal subject and from a patient with sickle cell anaemia, caused factor B and C3 cleavage and loss of haemolytic activity of factor B wehn incubated with fresh autologous serum. Under the same experimental conditions, preparations of erythrocyte stroma or of buffycoat lysates did not produce factor B and C3 cleavage. This reaction required Mg++ but not C1q or C4, indicating that the alternative complement pathway was activated.  (+info)

Serum heat-labile opsonins in systemic lupus erythematosus. (21/379)

To study possible mechanisms responsible for the increased susceptibility to infection of patients with active systemic lupus erythematosus (SLE), a study of the serum heat-labile opsonic capacity (HLOC) in such patients was undertaken. With leukocytes from normal donors, the sera of 12 of 30 patients with active SLE demonstrated decreased HLOC for E. coli 075. The phagocytic activity was partially restored by normal serum, suggesting that decreased HLOC was responsible for the defective phagocytosis. While 8 of 10 patients with active SLE and concomitant infections showed deficient opsonic capacity to E. coli 075, only 4 of 20 such patients without infections showed the defect (P = 0.01). None of 12 patients with inactive disease had deficient opsonic capacity. Similar results were obtained with S. aureus 502A as the test bacterium. In the patients surviving infection, recovery of normal serum opsonic capacity was rapid and usually coincided with an increase of serum complement to normal levels. In three patients with active SLE and infection, the causative microorganisms were isolated and opsonic capacity for these organisms tested with the individual patients' sera. In each case, sera obtained at the onset of the infectious episode had low opsonic capacity when compared with normal sera. Serum C3 proactivator levels were low in 9 of 11 sera with deficient opsonic capacity. However, similar low values were found in other SLE sera with normal HLOC, suggesting that other factors of the opsonic system were also depleted. Addition of the classical complement components C1, C4, C2, C3, and C5 to sera with deficient HLOC failed to restore activity. Addition of pure C3 proactivator also failed to restore activity. However, addition of C3 proactivator together with 50 degrees C-heated normal serum restored activity, indicating that factors active at the early steps of opsonic activation via the alternative pathway of complement were necessary to restore opsonic activity. These findings indicate that in active SLE, a decrease of components of the alternate pathway of complement activation results in an acquired defect of serum HLOC and perhaps other related complement-mediated functions. This defect may be an important factor in the increased susceptibility to infections of patients with active systemic lupus erythematosus.  (+info)

Accelerated nephrotoxic nephritis is exacerbated in C1q-deficient mice. (22/379)

C1q deficiency strongly predisposes to the development of systemic lupus erythematosus in humans and mice. We used the model of accelerated nephrotoxic nephritis in C1q-deficient mice to explore the mechanisms behind these associations. C1q-deficient mice developed severe glomerular thrombosis within 4 days of induction of disease, whereas wild-type mice developed mild injury. These findings suggest that C1q protects from immune-mediated glomerular injury. This exacerbated thrombosis was also seen in mice triply deficient in C1q, factor B, and C2, excluding a major pathogenic role for the alternative pathway of complement in this phenomenon. However, these mice did not develop elevated creatinine levels. No exacerbation of accelerated nephrotoxic nephritis was observed in mice doubly deficient in factor B and C2, suggesting a protective role for C1q against renal inflammation that is proximal to C2 activation. There were increased murine IgG deposits, neutrophil numbers, and apoptotic cells in the glomeruli of C1q-deficient mice compared with wild-type mice. Renal expression of genes encoding procoagulant proteins was also enhanced in C1q-deficient mice. The increased IgG deposits and apoptotic cells in the glomeruli of C1q-deficient mice suggest that the exacerbation of disease may be due to a defect in the clearance of immune complexes and/or apoptotic cells from their kidneys.  (+info)

Relative importance of C3b inactivator and beta 1H globulin in the modulation of the properdin amplification loop in systemic lupus erythematosus. (23/379)

Serum concentrations of C4, C3, factor B (B), properdin (P), C3b inactivator (C3bINA) and beta 1H globulin have been measured by radial immunodiffusion in sixty-two samples from thirteen patients with systemic lupus erythematosus (SLE). Significant reductions in the mean serum concentrations of C4 (classical pathway) B and P (alternative pathway) and C3 were found. In addition, the mean level of the control protein beta 1H, but not C3bINA, was reduced. Sera from thirteen patients taking during disease exacerbation (low C3) showed significantly lower levels of both C3bINA and beta 1H than sera taken from the same thirteen patients during disease remission (high C3). Serum concentrations of C3bINA correlated with B (P less than 0.005) but not C4, C3 or P, whereas levels of beta 1H correlated with C4 (P less than 0.01), B (P less than 0.005) and properdin (P less than 0.01). Serial measurements of the serum concentrations of C3bINA and beta 1H showed that levels of these protein fell during exacerbation, and such falls were more closely associated with diseases in the serum levels of the alternative pathways proteins than C4. It is concluded from these observations that serum concentrations of the control proteins C3bINA and beta 1H, especially the latter, control the extent of turnover of the alternative pathway in SLE. Metabolic studies are required to determine the causes of the decreased serum concentrations of these control proteins.  (+info)

Membrane-bound antibodies to bloodstream Trypanosoma cruzi in mice: strain differences in susceptibility to complement-mediated lysis. (24/379)

The Y, CL and other strains of Trypanosoma cruzi display different morphological and immunological characteristics. Such observations are here extended to the interaction of bloodstream forms of different strains of T. cruzi with components of the complement system. We demonstrate that the bloodstream forms of the Y and B strains, but not those of the CL strain, are lysed by normal human serum. Lysis is mediated by combined activities of the alternative and classical complement pathways. These activities are triggered by antibodies on the surface of the parasites as shown by: (a) binding of fluorescein or radiolabelled anti-mouse immunoglobulin to the parasite's membrane and (b) the finding that bloodstream forms from lethally irradiated mice can be sensitized and rendered susceptible to complement-mediated lysis by incubation with sera from acutely infected animals. Bloodstream forms of the CL strain also bear surface immunoglobulin and sensitizing antibodies are present in the sera of mice infected with this strain. However, CL trypomastigotes from acutely infected mice fail to be lysed by human or mouse complement unless the parasites are pre-incubated with sera from chronically infected animals. The basis of the different interactions between CL and Y trypomastigotes with antibodies and the complement system, and their biological significance are discussed.  (+info)