Type 1 diabetes: B-cell-derived antibodies prevent autoimmunity

Researchers have uncovered a novel mechanism underlying a previously reported discovery that infection with group A Streptococcus bacteria lowers the likelihood of getting Type 1 diabetes later in life.

The Journal of Immunology finds that group A Streptococcus immunization of neonatal mice enhanced clonal growth of innate-like B cells that generate antibodies against N-acetyl-D-glucosamine, or GlcNAc. GlcNAc is a glucose sugar derivative found in the cell wall of group A streptococci as well as antigens on insulin-producing pancreatic beta cells generated by GlcNAc posttranslational modifications.

The researchers from the University of Alabama in Birmingham discovered that the associations of lower Type 1 diabetes risk after group A Streptococcus infection were dependent on these GlcNAc-specific B-1 B cells. B-1 cells are a type of B cell in mice that produces natural antibodies, which are antibodies produced in the absence of infection. Such natural antibodies can contribute in the development of tolerance, the process by which the immune system learns to tolerate – rather than attack – its own tissues.

The discovery of the significance of B-1 B cells “demonstrates the potential for targeting the natural antibody repertoire in considering therapeutic strategies for Type 1 diabetes,” according to the study’s lead author, John Kearney, Ph.D., a professor in the UAB Department of Microbiology.

Autoimmune disorders, such as Type 1 diabetes, are caused by a failure to maintain tolerance. The immune system attacks and specifically destroys the insulin-producing beta cells of the pancreas in Type 1 diabetes. Insulin is a hormone that assists cells in using glucose for energy. The loss of insulin synthesis following beta cell death results in dangerously high levels of glucose in the blood, which can lead to disabilities such as blindness, heart disease, and kidney failure.

Initially, the UAB researchers demonstrated immunization of neonatal mice at 14 days of age with either a dead or living group. In comparison to controls, a Streptococcus protected them from Type 1 diabetes. Adult immunization of this mouse strain, which is prone to diabetes, failed to protect, indicating that timing was critical to protection.

The naive mice with diabetes displayed considerable B and T cell infiltration into the pancreas and a disruption of the membrane surrounding the pancreatic islets that contain beta cells at 10 to 12 weeks of age. The newborn immunized mice did not exhibit these pathological abnormalities.

The neonatally inoculated mice produced immunoglobulin M, or IgM, which bound to both group A carbohydrate and GlcNAc, and the mice also demonstrated clonal growth of otherwise rare group A carbohydrate-reactive B-1b B cell clonotypes.

To investigate prospective targets of the IgM antibodies, the UAB researchers produced group A carbohydrate-reactive monoclonal antibodies, and they discovered that the monoclonal antibodies identified insulin secretory granule-associated GlcNAc antigen sections, known as epitopes, on pancreatic beta cells. These carbohydrate-reactive monoclonal antibodies from group A were highly reactive with both human and mouse pancreatic islets.

These epitopes appeared to be produced during autophagosomal breakdown of mature carbohydrates, which is one of the processes in beta cell apoptosis, or programmed cell death. Experiments revealed that the GlcNAc-reactive B cell response to group A streptococci appeared to postpone Type 1 diabetes, possibly by facilitating effective clearance of apoptotic beta cells and, as a result, restricting activation of killer and helper T cells, which would eventually destroy viable beta cells. Indeed, binding of group A carbohydrate-reactive monoclonal antibodies to pancreatic islet cells suppressed T cell activation in ex vivo tests.

There was, however, a mystery.

The administration of a monoclonal antibody or pooled IgM from immunized mice alone did not protect naive mice from acquiring Type 1 diabetes. Thus, while IgM-producing B cells are important in preventing Type 1 diabetes, and while IgM antibody protects against T cell activation in test tube trials with isolated cells, IgM alone was unable to prevent Type 1 diabetes in naive mice.

The explanation to this riddle is that as Type 1 diabetes develops in mice, group A carbohydrate-reactive B-1 B cells exhibit an unusual proclivity to enter the pancreas. Neonatal vaccination raised the amount of activated group A carbohydrate-positive B lymphocytes specifically localized in the pancreas by 20-fold at 10 to 12 weeks of age. According to the researchers, the B cells can release IgM or other soluble mediators that protect the beta cells there.

While IgM alone was not protective, the researchers discovered that adoptive transfer of B cells from neonatally vaccinated animals with group A carbohydrate can greatly lower the incidence of Type 1 diabetes in recipient mice at 30 weeks of age.

“Collectively, our observations indicate a significant involvement of cryptic glycan epitopes in immunological recognition of senescent beta cells, and that clonal composition of the GlcNAc-specific B cell repertoire during early life can significantly influence immune responsiveness to Type 1 diabetes autoantigens,” Kearney said in a press release. “We postulate that natural antibody repertoire defects precede emergence of beta cell-specific autoantibodies associated with and currently used to determine the risk of Type 1 diabetes progression.”

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