Maternal provisions in type 1 diabetes: Evidence for both protective & pathogenic potential

Abstract

Maternal influences on the immune health and development of an infant begin in utero and continue well into the postnatal period, shaping and educating the child's maturing immune system. Two maternal provisions include early microbial colonizers to initiate microbiota establishment and the transfer of antibodies from mother to baby. Maternal antibodies are a result of a lifetime of antigenic experience, reflecting the infection history, health and environmental exposure of the mother. These same factors are strong influencers of the microbiota, inexorably linking the two. Together, these provisions help to educate the developing neonatal immune system and shape lymphocyte repertoires, establishing a role for external environmental influences even before birth. In the context of autoimmunity, the transfer of maternal autoantibodies has the potential to be harmful for the child, sometimes targeting tissues and cells with devastating consequences. Curiously, this does not seem to apply to maternal autoantibody transfer in type 1 diabetes (T1D). Moreover, despite the rising prevalence of the disease, little research has been conducted on the effects of maternal dysbiosis or antibody transfer from an affected mother to her offspring and thus their relevance to disease development in the offspring remains unclear. This review seeks to provide a thorough evaluation of the role of maternal microorganisms and antibodies within the context of T1D, exploring both their pathogenic and protective potential. Although a definitive understanding of their significance in infant T1D development remains elusive at present, we endeavor to present what has been learned with the goal of spurring further interest in this important and intriguing question.

Keywords: autoantibody; autoimmunity; dysbiosis; immunoglobulin; microbiome; tolerance.

Figure 1

Proposed mechanisms of autoimmune activation leading to insulitis. (A) Environmental triggers such as infection or prolonged antibiotic use can induce changes in the GI tract leading to dysbiosis, increased GI inflammation and impaired barrier integrity. Together, these changes promote microbial translocation across the epithelial lining and increase PAMP presence in secondary lymphoid organs such as the MLN and PLN. (B) Presentation of PAMPs to T lymphocytes in the MLN and PLN results in T and B lymphocyte activation and promotion of a pro-inflammatory environment. Impaired central and peripheral tolerance in genetically at-risk individuals can allow for the erroneous activation of autoreactive lymphocytes by multiple mechanisms, including molecular mimicry and bystander effects. (C) Enteric viruses can gain access to pancreatic islets, resulting in infection and death of beta cells. As infected cells die and release autoantigens, APC internalize these autoantigens and present them to lymphocytes in the PLN. Owing to ineffective peripheral tolerance, islet-reactive lymphocytes become activated and infiltrate the islets, promoting further beta cell destruction. (D) Activated islet-specific B lymphocytes undergo differentiation to plasma cells which enter systemic circulation and secrete islet-specific antibodies into the bloodstream. Detection of these autoantibodies is a clinical indicator preceding diagnosis of T1D. GI, gastrointestinal; PAMP, pathogen associated molecular patterns; MLN, mesenteric lymph nodes; PLN, pancreatic lymph nodes; APC, antigen presenting cell; Tfh, follicular helper T lymphocytes; Treg, regulatory T lymphocyte.

Figure 2

FcRn transport of maternal IgG. (A) FcRn expression in the placenta allows for the active transport of IgG from the mother’s bloodstream to the infant during gestation. If maternal IgG has bound antigen (Ab-Ag complex) this antigen will be transported to the infant as well, resulting in early antigenic exposure. (B) FcRn expression along the GI tract of the neonate can bind and transport maternal IgG and Ab-Ag complexes from breast milk across the intestinal barrier. These maternal antibodies can infiltrate local lymphoid tissues such as the MLN and PP. (C) Whether originating from maternal bloodstream or breast milk, IgG and Ab-Ag complexes can enter the infant’s circulation. Maternal IgG provides a source of passive immunity for the infant, neutralizing pathogens that would otherwise present a serious challenge for the underdeveloped neonatal immune system. (D) Maternal IgG and Ab-Ag complexes in infant circulation can gain access to various lymphoid organs where they can be taken up by APC via cell surface FcRn. Once endocytosed, the IgG can be recycled and the antigenic peptide presented to naive T lymphocytes. This early antigenic exposure generally results in a tolerogenic response, including the polarization and proliferation of CD4⁺ T lymphocytes to Treg. FcRn, neonatal Fc receptor; GI, gastrointestinal; MLN, mesenteric lymph nodes; PP, Peyer’s Patches; APC, antigen presenting cells; Treg, regulatory T lymphocytes.

Figure 3

Idiotypic/anti-idiotypic network hypothesis. (A) The antigen binding site of an antibody is referred to as the idiotope. Idiotypic antibody Ab1 recognizes and binds epitope X on autoantigen X. In T1D, autoantigen X is frequently a beta cell protein such as insulin, glutamic acid decarboxylase (GAD), or tyrosine phosphatase-related insulinoma-associated 2 molecule (IA-2). Detection of T1D-associated autoantibodies is routinely used as a diagnostic indicator of disease. (B) The idiotypic network postulates that antibodies can be raised against the idiotope of Ab1. In the context of autoimmunity, these anti-idiotypic (anti-Id) antibodies (Ab2) compete with autoantigen X for binding sites on Ab1, resulting in Ab1 neutralization and limiting antibody-mediated damage to target cells. Anti-Id antibodies have been detected in healthy individuals and T1D patients, but are not routinely measured. (C) During the neonatal period, binding of anti-Id Ab2 to the B cell receptor of Ab1-bearing B lymphocytes leads to their suppression. Similarly, anti-Id antibodies can suppress T lymphocytes via binding to their T cell receptors.