Takatoshi Kobayakawa

Imbalance towards Th1 predominance is associated with acceleration of lupus-like autoimmune syndrome in MRL mice.

To investigate the respective roles of Th1 and Th2 cells in the pathogenesis of lupus-like autoimmune disease, we have analyzed the spontaneous and antigen-induced productions of IgG1 vs IgG2a and IgG3 subclasses in relation to the mRNA expression of INF-gamma (Th1 cytokine promoting IgG2a and IgG3 production), IL-4 (Th2 cytokine promoting IgG1 production), and IL-10 (Th2 cytokine) in CD4+ T cells from lupus-prone MRL mice. For this purpose, two paired sets of MRL mice were chosen for the comparison of these parameters: (a) MRL-lpr/lpr (lpr for lymphoproliferation) and its recently described substrain with a prolonged survival, termed MRL-lpr/lpr.ll (ll for long lived) and (b) MRL male mice bearing the Yaa (Y-linked autoimmune acceleration) gene (MRL.Yaa) with an accelerated disease and their male counterparts lacking the Yaa gene. We demonstrate herein that the accelerated development of lupus-like autoimmune disease in MRL-lpr/lpr and MRL.Yaa mice, as compared with MRL-lpr/lpr.ll and MRL-+/+ mice, respectively, was correlated with an enhanced expression of IFN-gamma vs IL-4 and IL-10 mRNA in CD4+ T cells, which paralleled with an increase of spontaneous and foreign T cell-dependent antigen-induced productions of IgG2a and IgG3 vs IgG1 antibodies. These data suggest that an imbalance towards Th1 predominance may play a significant role in the acceleration of lupus-like autoimmune disease in MRL mice.

Role of neutrophils in murine cryoglobulinemia

Abstract. Murine IgG3 anti-IgG2a rheumatoid factor (RF) monoclonal antibodies (mAb) with cryoglobulin activity, are able to induce, in normal mice, skin leukocytoclastic vasculitis and lupus-like glomerulonephritis resembling ‘wire-loop’ lesions (subendothelial immune deposits). The development of glomerular, but not skin, lesions in immunoglobulin-deficient mice (lacking the corresponding IgG2a autoantigen) receiving IgG3 RF cryoglobulins indicates that the RF activity of IgG3 monoclonal cryoglobulins and subsequent formation of IgG3-IgG2a immune complexes play a critical role in the development of skin vasculitis. In contrast, nephritogenic activity is solely contributed by IgG3-associated cryoglobulin activity. Polymorphonuclear leukocyte (PMN) infiltration is one of the major pathologic changes observed in both types of lesions. Treatment with mAbs against the adhesion molecules leukocyte function-associated antigen 1 (LFA-1) and intercellular adhesion molecule 1 (ICAM-1) (both known for their involvement in PMN-endothelial cell interaction) inhibits the development of skin vascular lesions. However, it has no effect on the generation of glomerulonephritis. Apparently, adhesion molecule requirements for PMN interaction with glomerular capillary endothelial cells are different from those for PMN infiltration of the skin. However, the PMN depletion experiment has clearly shown that PMNs play an active role in the development of ‘wire-loop’ glomerular lesions. In the absence of the glomerular PMN infiltration, IgG3 RF cryoglobulins induce a different type of glomerular lesion, characterized by voluminous intracapillary thrombi and mesangial deposits, yet lacking subendothelial deposits. This is consistent with the fact that the latter lesions can be induced by certain IgG3 mAbs, which are unable to provoke glomerular PMN infiltration. Finally, the activation of the complement system does not appear to play a major role in either skin or glomerular lesions induced by IgG3 RF cryoglobulins.

IgM rheumatoid factors in Guatemalan onchocerciasis

The possible presence of IgM Rheumatoid factors (RF) and anti-DNA antibodies was investigated in sera of patients with Guatemalan onchocerciasis. The mean value of IgM RF in the patients was found to be significantly higher than that in controls and 10 out of 57 patients had increased levels of IgM RF. In addition, serum IgM levels in those 10 patients with increased levels of IgM RF were significantly elevated. In contrast, no significant increase of serum anti-single-stranded (ssDNA) and double-stranded DNA (dsDNA) antibodies were found in the patients.

MHC-linked Control of Murine SLE

Systemic lupus erythematosus (SLE) is a disorder of generalized autoimmunity characterized by the formation of a variety of autoantibodies and subsequent development of severe glomerulonephritis [1]. It is now well established that SLE is under some form of polygenic control, in which several genetic factors independently contribute to the overall susceptibility and progression of the disease. Studies suggest that heterogeneous combinations of multiple diseaseassociated genes operate in a threshold manner to generate the disease [2–4]. Among such genetic factors, the importance of the genes encoded within or closely linked to the MHC locus has been shown. However, it has not yet been determined whether the development of lupus-like disease is predominantly mediated by MHC class II genes and which other genes within MHC may contribute to this effect.

Circulating Immune Complexes and Their Possible Relevance to Other Immunological Parameters in Guatemalan Onchocerciasis

Circulating immune complexes (CIC) were demonstrated in sera of Guatemalan patients with onchocerciasis by Raji cell radioimmunoassay. 44% of patients but none of controls had abnormally high concentrations of CIC in their sera. The increased concentrations of CIC were found more frequently in patients with lower density of microfilariae in their skin biopsies. Patients with higher concentrations of CIC appeared to have increased titers of serum antibodies to Onchocerca volvulus. A depression of both humoral immune response to tetanus toxoid and delayed hypersensitivity reaction to PPD were found in patients with onchocerciasis. CIC may be involved in modulation of the immune response in onchocerciasis.

Protection of murine systemic lupus erythematosus by an I-E α-chain transgene

SYSTEMIC lupus erythematosus (SLE) is a disorder of generalized autoimmunity characterized by the formation of a variety of autoantibodies and the development of lethal glomerulonephritis. It is now well established that SLE is under some form of polygenic control in which multiple genetic factors independently contribute to the overall susceptibility of individuals to the disease. The gene(s) encoded within the major histocompatibility complex (MHC) acts as one of the major genetic elements contributing to the susceptibility of murine SLE. It has been demonstrated that the lupus susceptibility is more closely linked to the I-E H-2 haplotype than to the I-E H-2 and H-2 haplotypes in lupus-prone BXSB and (NZB 3 BXSB)F1 hybrid mice. 1,2

Relevance of Polyclonal Antibody Formation to the Development of Autoimmunity: The Model of African Trypanosomiasis

There is an induction of anti-DNA antibodies in mice following the administration of bacterial lipopolysaccharides, Dextran sulfate and PPD, which is closely associated with the property of these substances to trigger a polyclonal B cell activation. In the experiments model of African trypanosomiasis there is also an intense polyclonal antibody synthesis paralleled by the formation of several autoantibodies: anti-DNA, anti-bromelain treated mouse red blood cells and antithymocyte antibodies.