Clinical, molecular and cellular characteristics of an Australian cohort with primary antibody deficiency and autoimmunity

Abstract

Primary non-congenital antibody defects including common variable immune deficiency (CVID) are the most common forms of primary immune deficiency. These disorders are characterised by recurrent infection as well as immune dysregulation that results in autoimmunity and spontaneous inflammation. This thesis reports research into the mechanisms of primary antibody deficiency, and the intersection between autoimmunity and immune deficiency. The work described was made possible by a national cohort of patients with primary antibody deficiency (Australian New Zealand Antibody Deficiency Allele Study). The clinical and laboratory characteristics of the first 193 patients recruited to the study are described. The clinical presentations of members of this cohort are similar to those reported elsewhere, although several new features are reported. We describe atopic disease in patients with low or absent serum IgE. Chronic dermatitis and furunculosis were relatively common complications. Furthermore, the development of furunculosis was associated with non-infective gastrointestinal inflammation. Individuals with PAD who had lower total serum immunoglobulin levels appear to be at increased risk of clinically detectable granulomatous disease. The cohort was screened for novel genetic defects, specifically in miRNA genes and 3'-UTR regions of target genes implicated in B cell development. Although novel mutations were discovered in these genes, none were found to be physiologically relevant in the pathogenesis of primary antibody deficiency. Finally, the genetic and cellular basis of the association between antibody deficiency and autoimmunity was investigated. Two allelic variants of TNFRSF13B segregated with primary antibody deficiency. In addition, the association between these two variants and systemic autoimmunity was similar, irrespective of antibody phenotype. Conversely, the 1858T allele of PTPN22 segregates with various autoimmune diseases. This study reports that this allele is strongly associated with autoimmunity in patients with primary antibody deficiency. The cellular basis of autoimmunity in primary antibody deficiency remains uncertain, although an increase in CD19+CD21low B cells has been described in this subset. The mechanism for this expansion, and indeed the ontogeny of this population remains contentious. A novel phenotyping panel was employed to characterise these CD19+CD21 low B cells after validating this panel in peripheral adult blood, cord blood, and tonsils. CD19+CD21 low B cells were characterised in subjects with autoimmunity alone (systemic lupus erythematosus) and primary antibody deficiency. CD19+CD21 low B cells are heterogeneous. In those with autoimmunity alone, the CD19+CD21 low B cells were enriched for anergic and pre-germinal centre B cells while in some patients with antibody deficiency, CD19+CD21 low B cells arose in the absence of naive or transitional B cells, suggesting that they arose directly from early precursors. These CD19+CD21 low B cell phenotypes were not accounted for by the autoimmune allelic variant of PTPN22.