Preclinical stage abundance and nuclear antigen reactivity of fecal Immunoglobulin A (IgA) varies among males and females of lupus-prone mouse models

Abstract

Systemic lupus erythematosus (SLE) is characterized by the production of pathogenic autoantibodies with nuclear antigen (nAg) specificity. Using (SWRxNZB)F1 (SNF1) mice, we showed higher levels of IgA production in the intestine and the nAg reactivity of fecal IgA under lupus susceptibility. Here, we determined if the fecal IgA abundance and nAg reactivity are higher in, different among, various lupus-prone preclinical models (MRL/lpr, NZBxNZW-F1, SNF1, NZM2410 and NZM2328). We also determined if the fecal IgA nAg reactivity at pre-seropositive ages correlates with the eventual serum autoantibody levels in males and females of these mouse models. We show that age dependent increase in the abundance and nAg reactivity of fecal IgA can vary among different lupus-prone mouse models. Importantly, fecal IgA in these mice show significant levels of nAg reactivity, starting as early as at juvenile age. Furthermore, the pre-seropositive stage nAg reactivity of fecal IgA in most lupus-prone strains correlates well with that of eventual, seropositive stage systemic autoantibody levels. Gender differences in serum autoantibody levels were preceded by similar differences in the fecal IgA abundance and nAg reactivity. These observations suggest that fecal IgA features, nAg reactivity particularly, could serve as a biomarker for early prediction of the eventual systemic autoimmunity in lupus-prone subjects.

Fecal immunoglobulin A (IgA) and its subclasses in systemic lupus erythematosus patients are nuclear antigen reactive and this feature correlates with gut permeability marker levels

“…In this regard, it would be informative to determine if fecal IgA and subclass features and Zonulin alter during active disease flares in SLE patients. Furthermore, although additional studies using longitudinal samples from subjects who are susceptible to SLE are needed, our current observations in the context of our preclinical studies [6,7] suggest the potential biomarker value of fecal IgA features alone or along with Zonulin levels, in predicting the ongoing autoimmune process, if any, in at-risk subjects.…”

“…High levels of circulating autoantibodies and immune-complexes (IC), and IC deposition in the kidney causing glomerulonephritis are the hallmarks of SLE [1,2]. Our preclinical studies using lupus-prone mice have shown: 1) that minor dietary deviations can alter the composition of gut microbiota and the lupus-like disease progression [3], 2) a potential contribution of pro-inflammatory immune response, including higher frequencies of plasma cells, initiated in the gut mucosa to the disease process and gender bias [4,5], 3) higher frequencies of IgA-autoantibody producing cells in the gut mucosa, and 4) higher abundance and nAg reactivity of fecal IgA at pre-seropositive and -clinical stages [6,7]. Importantly, higher gut permeability and microbial translocation have been implicated in the initiation and/or progression of autoimmunity in at risk subjects [8,9].…”

Fecal immunoglobulin A (IgA) and its subclasses in systemic lupus erythematosus patients are nuclear antigen reactive and this feature correlates with gut permeability marker levels

“…High levels of circulating autoantibodies and immune-complexes (IC), and IC deposition in the kidney causing glomerulonephritis are the hallmarks of SLE [1, 2]. Our preclinical studies using lupus-prone mice have shown: 1) that minor dietary deviations can alter the composition of gut microbiota and the lupus-like disease progression [3], 2) a potential contribution of pro-inflammatory immune response, including higher frequencies of plasma cells, initiated in the gut mucosa to the disease process and gender bias [4, 5], 3) higher frequencies of IgA-autoantibody producing cells in the gut mucosa, and 4) higher abundance and nAg reactivity of fecal IgA at pre-seropositive and -clinical stages [6, 7]. Importantly, higher gut permeability and microbial translocation have been implicated in the initiation and/or progression of autoimmunity in at risk subjects [8, 9].…”