Humoral immune response in hereditary and overt diabetes mellitus

Abstract

The inbred diabetic mutant mouse, C57BL/KsJ db +/db + (db +/db +), spontaneously develops diabetes mellitus when allowed food ad libitum. However, restriction of food intake prevents the expression of this genetic predisposition for diabetes. This experimental design has been used previously to demonstrate a deficient neutralizing antibody response to coxsackievirus B4 (CB4) in mutants with the genetic predisposition only. These observations demonstrate that in the genetically predisposed diabetic mutant, deficient humoral immunity extends further to a general impairment in both total IgM and IgG production after CB4 infection. Furthermore, these mice are unable to produce a virus-specific IgG response but do show a high level of nonspecific antibody suggesting a polyclonal activation following CB4 challenge. In addition, we observed an increase in the number of spleen IgM antibody-forming cells to sheep erythrocytes (SRBC) in the overtly diabetic animal following CB4 infection with little change apparent in the genetically predisposed animal after infection. These results were identical to the changes seen in total spleen cell numbers. Our animal model provides an opportunity to distinguish between the genetic predisposition to diabetes and the overt disease and suggests that some of the immune impairment found prior to diabetes onset may be partially diminished afterwards.

A New Look at Viruses in Type 1 Diabetes

“…Notwithstanding these strain differences, the capacity of Coxsackie B4 virus to induce diabetes appears to be definitely influenced by the genetic background of the host. Genetic studies showed that the 'db' diabetic mutation on chromosome 4 exerted the most effect on susceptibility and host response to Coxsackie B4 virus [204,205] and was associated with an impaired humoral response to Coxsackie B4 viral infection as infected mice did not develop an adequate level of anti-Coxsackie B4 IgM and IgG antibodies [206,207]. The animals were also found to be deficient in absolute and relative numbers of splenic lymphocyte subsets [208].…”

Leptin Modulates the Survival of Autoreactive CD4+ T Cells through the Nutrient/Energy-Sensing Mammalian Target of Rapamycin Signaling Pathway

“…Leptin-deficient (ob/ob) mice and leptin receptor-deficient mice (db/db) mice display numerous immune abnormalities (14,15), including CD4 + T cell lymphopenia, increased numbers of natural regulatory T cells, and a resistance to autoimmune disorders including experimental autoimmune encephalomyelitis (EAE), experimental colitis, Ag-induced arthritis, and type 1 diabetes (16).…”

“…An uncontrolled expansion of autoreactive T cells could favor autoimmunity (20)(21)(22)(23)(24), but in ob/ob mice, CD4 + lymphopenia does not associate with homeostatic proliferation of T cells and autoimmunity (14)(15)(16).…”

Leptin Receptor Expression and Signaling in Lymphocytes: Kinetics During Lymphocyte Activation, Role in Lymphocyte Survival, and Response to High Fat Diet in Mice

“…Recent experimental evidence (11) supports a direct role for leptin in the regulation of immunity. Leptin-deficient mice (ob/ob), 3 leptin receptor (ObR)-deficient mice (db/db) mice, as well as mice with starvation-induced leptin deficiency, display an array of immune abnormalities (12,13). Administration of leptin reverses the starvation-induced immunosuppression in vivo, and leptin enhances T cell proliferation and Th 1 proinflammatory cytokine production in vitro, conditional on the presence of a functional ObR (14).…”