Identification of a novel spontaneous mouse model of celiac disease.  Using an IgA-deficient mouse to explore the impact of IgA-deficiency under homeostatic conditions we have identified a constellation of physiological defects, including intestinal malabsorption (a hallmark feature of CD), that strongly suggests that our mouse model represents the first spontaneous mouse model of ‘sero-negative’ celiac disease in humans (manuscript forthcoming). This provides a critical tool for future studies seeking to identify novel therapies to treat this disease. We are now excited to begin studies exploring the use of probiotic therapy to alleviate intestinal malabsorption in our model!

Identification of a novel spontaneous mouse model of celiac disease. Using an IgA-deficient mouse to explore the impact of IgA-deficiency under homeostatic conditions we have identified a constellation of physiological defects, including intestinal malabsorption (a hallmark feature of CD), that strongly suggests that our mouse model represents the first spontaneous mouse model of ‘sero-negative’ celiac disease in humans (manuscript forthcoming). This provides a critical tool for future studies seeking to identify novel therapies to treat this disease. We are now excited to begin studies exploring the use of probiotic therapy to alleviate intestinal malabsorption in our model!

Gut Antibody Deficiency And Celiac Disease (CD)

IgA deficiency is the most common form of primary immunodeficiency and is 10-15 times more common in patients with CD. CD is an inflammatory disorder in the gut that results in intestinal malabsorption. Ironically, one of the most utilized diagnostic tests of CD is to measure serum concentrations of antibodies that are reactive to gliadin (the major antigenic component of wheat thought to be a primary driver of disease). Thus, many CD patients may go undiagnosed because they test negative for such biomarkers due to an underlying antibody deficiency. CD in the absence of a strong antibody response to gluten antigens is termed ‘sero-negative’ CD (SNCD). SNCD has been associated with antibody-deficiencies in humans. Currently, there is no available mouse model to study SNCD.

 
 
The contribution of T-cell-independent and T-cell-dependent anti-commensal IgA responses in the gut is controversial.  B-cell-intrinsic MHCII signaling can be thought of as a critical factor mediating competition among B cell clones for T cell ‘help’, which is required for survival of developing B cells during germinal center reactions in the gut. Both the quality and quantity of MHCII:peptide complexes on the surface of different B cells can influence their ability to effectively interact with T cells to gain this survival advantage. We are currently utilizing conditional knockout mouse models to explore this phenomenon to determine how it influences IgA antibody diversity and IgA-mediated sculpting of the microbiome.

The contribution of T-cell-independent and T-cell-dependent anti-commensal IgA responses in the gut is controversial. B-cell-intrinsic MHCII signaling can be thought of as a critical factor mediating competition among B cell clones for T cell ‘help’, which is required for survival of developing B cells during germinal center reactions in the gut. Both the quality and quantity of MHCII:peptide complexes on the surface of different B cells can influence their ability to effectively interact with T cells to gain this survival advantage. We are currently utilizing conditional knockout mouse models to explore this phenomenon to determine how it influences IgA antibody diversity and IgA-mediated sculpting of the microbiome.

B-cell-Intrinsic MHCII Signaling and IgA-mediated selection in the Gut

Classical MHC class II (MHCII) genes encode cell-surface glycoproteins that are expressed on the surface of a restricted set of cells (antigen presenting cells like macrophages, dendritic cells, AND B CELLS!). These molecules present small fragments of protein antigens (peptides) to T cells thereby controlling T cell activation. However, MHCII is also important for clonal selection of B cells (ie. favoring the survival of some clones over others) during germinal center (GC) reactions in lymphoid follicles. With a focus on the gut mucosal immune system, we are using a combination of conditional knockout and fluorescent lineage-tracing mouse models to unravel this complex process. Ultimately we seek to understand how B-cell-intrinsic MHCII signaling controls competition among GC B cells, and how this in turn controls IgA antibody repertoire diversity and the breadth of microbial species that can be bound by IgA. This is important to understand because polymorphisms at MHCII loci are the strongest genetic risk factors for IgA deficiency in humans. Therefore, understanding how MHCII influences gut IgA responses is fundamental to understanding the pathophysiological consequences of IgA deficiency.

 
 
 
Microbial network analysis of the ‘core’ fecal microbiota of MHC congenic BALB/c mice.  Notice the more complex interactions (represented by the number of lines connecting dots (ie. species) within MHC heterozygote communities (bottom row). In a forthcoming manuscript we discuss the possibility that MHC heterozygosity may be favored evolutionarily by promoting a more beneficial microbiome. H2 refers to the mouse MHC region and the superscripted characters denote H2 haplotypes.

Microbial network analysis of the ‘core’ fecal microbiota of MHC congenic BALB/c mice. Notice the more complex interactions (represented by the number of lines connecting dots (ie. species) within MHC heterozygote communities (bottom row). In a forthcoming manuscript we discuss the possibility that MHC heterozygosity may be favored evolutionarily by promoting a more beneficial microbiome. H2 refers to the mouse MHC region and the superscripted characters denote H2 haplotypes.

MHC Heterozygosity and the Microbiome

MHCII genes are some of the most polymorphic genetic loci in humans with thousands of alleles circulating in the human population. The maintenance of this genetic diversity seems paradoxical given the central role these molecules play in adaptive immunity. This has long been a puzzle to Evolutionary Biologists and debate continues today regarding what constitutes the major force of natural selection favoring genetic variation at these loci. One possibility is that this variation enhances the ability of individuals to control microbiome composition and function through antibody responses. This research represents a continuation of Dr. Kubinak’s keen interest in MHC gene evolution.