Objective
Rheumatoid arthritis (RA) is considered to be a prototypical autoimmune disorder. Several mechanisms have been proposed for the known pathologic function of B cells in RA, including antigen ...presentation, cytokine secretion, and humoral immunity. The aim of this study was to address the function of B lymphocytes in experimental arthritis.
Methods
We mapped the adaptive immune response following collagen‐induced arthritis (CIA). We subsequently monitored these responses and disease outcomes in genetically modified mouse strains that lack mature B cell or germinal center (GC) functionality in a B cell–intrinsic manner.
Results
Following primary immunization, the draining lymph nodes broadly reacted against type II collagen (CII) with the formation of GCs and T cell activation. Mice that lacked mature B cell function were fully protected against CIA and had a severely attenuated ability to mount isotype‐switched humoral immune responses against CII. Almost identical results were observed in mice that were selectively deficient in GC responses. Importantly, GC‐deficient mice were fully susceptible to collagen antibody–induced arthritis.
Conclusion
We identified GC formation and anticollagen antibody production as the key pathogenic functions of B cells in CIA. The role of B cells in RA is likely to be more complex. However, targeting the GC reaction could allow for therapeutic interventions that are more refined than general B cell depletion.
The initiation, commitment, and terminal differentiation of the B cell lineage is stringently controlled by the coordinated action of various transcription factors. Among these,
has previously been ...implicated in regulating early B lymphopoiesis, humoral immune responses to phosphocholine, and furthermore to promote the B1 over the B2 cell lineage. We have now interrogated the function of
in the adult mouse using conditional mutagenesis. We demonstrate that loss of
does not affect early B cell development or lineage commitment but rather loss of this transcription factor results in a broad expansion of bone marrow B lymphopoiesis in a manner that reflects its developmental expression pattern. Furthermore, loss of
resulted in expanded splenic B cell numbers with the exception of the B1 lineage that was maintained at normal numbers. However, B1a lymphoyctes were reduced in the peritoneal cavity. In addition, antibody responses to phosphocholine were attenuated in the absence of
. Hence, functional
is required in mature B cells for specific immune responses and for generating normal numbers of B cells in a subset dependent manner.
Objective- Dyslipidemia is a component of the metabolic syndrome, an established risk factor for atherosclerotic cardiovascular disease, and is also observed in various autoimmune and chronic ...inflammatory conditions. However, there are limited opportunities to study the impact of acquired dyslipidemia on cardiovascular and immune pathology. Approach and Results- We designed a model system that allows for the conversion to a state of acute hyperlipidemia in adult life, so that the consequences of such a transition could be observed, through conditionally deleting APOE (apolipoprotein E) in the adult mouse. The transition to hypercholesterolemia was accompanied by adaptive immune responses, including the expansion of T lymphocyte helper cell 1, T follicular helper cell, and T regulatory subsets and the formation of germinal centers. Unlike steady-state Apoe
mice, abrupt loss of APOE induced rapid production of antibodies recognizing rheumatoid disease autoantigens. Genetic ablation of the germinal center reduced both autoimmunity and atherosclerosis, indicating that the immune response that follows loss of APOE is independent of atherosclerosis but nevertheless promotes plaque development. Conclusions- Our findings suggest that immune activation in response to hyperlipidemia could contribute to a wide range of inflammatory autoimmune diseases, including atherosclerosis.
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