Back-pack mice as a model of renal mesangial IgA dimers deposition.

Mesangial IgA in IgA nephropathy are dimers with a J chain but no poly-Ig receptor. This molecular structure has led to the hypothesis that these IgA are issued from the lamina propria of mucosal areas, reaching the kidney by way of the peripheral blood. The availability of hybridomas producing IgA dimers provided an opportunity to test this hypothesis in a new experimental model of IgA nephropathy. Mice were injected subcutaneously (back-pack mice) or intraperitoneally with hybridoma cells secreting either monoclonal IgA dimers, or monoclonal IgA monomers. The influence of immune complex formation was also tested in both these models. Renal IgA deposition was investigated 12 days after the injection of hybridoma cells. Backpack mice developed highly vascularized subcutaneous tumors. Mesangial IgA deposits were observed only in dimeric IgA hybridoma back-pack animals. No significant staining was observed in glomeruli from animals injected with hybridoma cells producing monomeric IgA. None of the hybridomas induced mesangial deposition when injected intraperitoneally. This animal model demonstrates the capacity of circulating IgA dimers to spontaneously form mesangial deposits and contributes to confirm the involvement of abnormalities of mucosal immunity in the pathogenesis of IgA nephropathy.

Anti-myelin oligodendrocyte glycoprotein B-cell responses in multiple sclerosis.

Humoral auto-immunity to the myelin oligodendrocyte glycoprotein (MOG) is likely involved in the pathogenesis of multiple sclerosis (MS). In 44 MS patients and 30 controls, Ig-producing B cells were identified by their isotype and as MOG-specific spot-forming cells (SFC). Peripheral anti-MOG antibodies were assayed in ELISA as well as anti-butyrophilin antibodies to investigate for molecular mimicry. MS patients had significantly higher levels of IgA- and MOG-SFC than controls, as well as significantly higher antibody responses to MOG and butyrophilin. These data provide added support for the implication of anti-MOG humoral immunity in the pathophysiology of MS, and suggest a balance of systemic (anti-self) and mucosal (environment-modulated) immune reactions in an attempt at regulating the pathogenic specific immune response.

Enhanced expression of L-selectin on peripheral blood lymphocytes from patients with IgA nephropathy.

To investigate the homing characteristics of T and B lymphocytes which could explain the abnormal partition of IgA-producing cells in tonsils and bone marrow from patients with IgA nephropathy (IgAN), the expression of leucocyte adhesion molecules (CD11a, CD29, CD49d, CD62L, CD31) was assessed using flow cytometry on peripheral blood leucocytes from patients with biopsy-proven IgAN and controls. Higher proportions of T and B lymphocytes expressing higher amounts of L-selectin, as well as higher proportions of B cells expressing more CD31 were evidenced in IgAN patients. Conversely, serum levels of sCD62L were not different from controls, but significantly higher than serum levels in patients suffering from other renal diseases. We hypothesize that this over-expression of CD62L and CD31 may be involved in an enhanced efficiency of lymphoid cells homing to lymphoid tissues in this disease.

High levels of soluble intercellular adhesion molecule-1 (ICAM-1) in crevicular fluid of periodontitis patients with plaque.

The intercellular adhesion molecule-1 (ICAM-1) is a membrane-bound molecule involved in cell-cell adhesive interactions which is upregulated on inflammatory epithelial cells. The levels of soluble ICAM-1 (sICAM-1) shed into the gingival crevicular fluid (GCF) were studied in healthy patients and patients with gingivitis, adult periodontitis or rapidly progressive periodontitis, using an ELISA technique. Clinical parameters including plaque index, gingival index, probing depth, and bleeding on probing were recorded following careful sampling of GCF with standardised filter strips. In GCF, sICAM-1 levels were higher for patients with plaque (p=0.04) and for patients with inflammation (p=0.02), but did not correlate with disease classifications. These results suggest that elevated GCF sICAM-1 levels may represent increased shedding of this molecule in the interstitial fluid as a result of membrane-bound ICAM-1 upregulation on ICAM-1 gingival-bearing cells in relation with plaque accumulation and inflammation.

Serum anti-rabbit and anti-horse IgG, IgA, and IgM in kidney transplant recipients.

BACKGROUND: The therapeutic efficacy of horse antilymphocyte globulins (ALG) or of rabbit antithymocyte globulins (ATG), used for both the prevention and treatment of allograft rejection has been well documented. However, clinical use of these heterologous antibodies can result in the production of antibodies against horse or rabbit proteins and in the development of serum sickness via circulating immune complexes. METHODS: We studied the production of human IgG, and IgM anti-rabbit and anti-horse globulins, in 240 serum samples from 111 kidney transplant recipients, of whom 89 were treated with ALG or ATG (Mérieux-France) as prophylaxis. RESULTS: Up to 8.9% of the patients had anti-ALG and/or -ATG antibodies before the first transplantation. This proportion increased significantly after. Preimmunization did not appear to be predictive of the occurrence of clinical serum sickness, yet sensitization increased, after transplantation, in up to 71% of the subjects who developed this disorder (P = 0.02). In patients receiving a second transplant, pretransplantation antibody levels were not modified by the immunosuppressive therapy applied. No relationship was found between early rejection and antiglobulin antibodies. CONCLUSIONS: Serum anti-rabbit and/or -horse antibodies were demonstrated in a significant proportion of kidney recipients, even before transplantation, possibly due to environmental exposure. A classical pattern of IgM increase was observed when the patients developed an immune response to ALG or ATG, and an IgA response after ALG. These results suggest that patients receiving ALG/ATG should be monitored for the production of anti-ALG/ATG immunoglobulins.

Enhanced expression of CD31 and CD54 on tonsillar high endothelial venules in IgA nephropathy.

Abnormalities in the partition of IgA- and IgG-producing cells in the tonsils of patients with IgA nephropathy have been suggested to result from a dysregulation of cell trafficking and homing through high endothelial venules in this lymphoid tissue. In order to document such adhesion anomalies, we used the 36 monoclonal antibodies of the cell adhesion molecules subpanel of the Fifth International Workshop on Leukocyte Differentiation Antigens on frozen sections of tonsils from 10 patients and 15 controls. This allowed us to describe the partition of cell adhesion molecules in human tonsils and to demonstrate a significant enhancement of CD31 and CD54 expression on high endothelial venules of tonsils from patients with IgA nephropathy. These observations are in keeping with the hypothesis of an increased lymphocyte recruitment in tonsils in this disease.

Low levels of spontaneously activated peripheral IgA-secreting cells in nontransplanted IgA nephropathy patients.

The pathognomonic presence of IgA in the glomerular mesangium of patients with IgA nephropathy (IgAN) suggests an abnormal control of IgA metabolism in this disease that could be modified in transplanted IgAN patients. Alterations of IgA production have been demonstrated in both bone marrow samples and mucosae-associated tissues from IgAN patients, but the analysis of IgA production by peripheral B lymphocytes in culture has yielded conflicting results, some investigators showing an enhanced secretion of IgA and others reporting similar data as with control samples. Little is known about the endogenous activation state of B cells in IgAN, which can be approached by analyzing peripheral Ig-producing cells, a number of which are recirculating between lymphoid organs. In the present study, two methods were applied to appreciate the numbers of spontaneously activated peripheral B cells. The ELISPOT method provided information about short-term secretion of Igs. Intracytoplasmic immunofluorescence for IgA allowed to identify IgA-containing cells, either as short-rimmed immunocytes or as brightly stained immunoblasts with an enlarged cytoplasm. These cells were enumerated in IgAN patients (n = 31), transplanted IgAN patients (n = 27), control patients with other biopsy-proven renal diseases (nontransplanted, n = 48; transplanted, n = 38), and in healthy individuals (n = 18). The number of IgA spot-forming cells obtained in the control groups (1,251 +/- 95 cells/10(6) lymphocytes [mean +/- SE]) was consistent with those in similar previously reported studies, but differed significantly (P = 0.01) from those observed in nontransplanted IgAN patients, who had a surprisingly lower number of such cells (699 +/- 97 cells/10(6) lymphocytes); the number of IgA spot-forming cells in the transplanted IgAN patients (1,355 +/- 182 cells/10(6) lymphocytes) did not differ from that in the control groups. The same pattern was seen for IgA-containing immunoblasts. There was no difference in IgG (overall, 214 +/- 13 cells/10(6) lymphocytes) and IgM (overall, 61 +/- 10 cells/10(6) lymphocytes) spot-forming cell numbers between the five groups of individuals tested, suggesting that the anomaly noted in IgAN patients was not related to technical problems and that this could be a new feature of this renal disease. The normal levels of spontaneously activated peripheral IgA-producing cells found in transplanted IgAN patients suggest that immunosuppressive treatments could interfere with the anomalies of IgA metabolism in this disease.