From Systemic T Cell Self-Reactivity to Organ-Specific Autoimmune Disease via Immunoglobulins

Abstract

Rheumatoid arthritis is a common and debilitating autoimmune disease whose cause and mechanism remain a mystery. We recently described a T cell receptor transgenic mouse model that spontaneously develops a disease with most of the clinical, histological, and immunological features of rheumatoid arthritis in humans. Disease development in K/BxN mice is initiated by systemic T cell self-reactivity; it requires T cells, as expected, but B cells are also needed, more surprisingly. Here, we have identified the role of B cells as the secretion of arthritogenic immunoglobulins. We suggest that a similar scenario may unfold in some other arthritis models and in human patients, beginning with pervasive T cell autoreactivity and ending in immunoglobulin-provoked joint destruction.

Evaluation of therapeutic targets in animal models of arthritis: How does it relate to rheumatoid arthritis?

“…A transient arthritis can be induced by intraperitoneal injection of serum from K/BxN mice, resulting in the influx of inflammatory cells, hyperplasia of synoviocytes, pannus formation, and cartilage destruction in the recipient mice (65). Inflammation in the joints resolves, unless mice are repeatedly injected with K/BxN serum.…”

Systemic humoral autoimmunity but joint‐specific inflammation: The syndrome of rheumatoid arthritis

“…Arthritis does not develop in the MT mutant mouse, which lacks B cells (6,7). Further studies established that direct interaction of T cells and B cells through CD40/CD40L is necessary for the elaboration of arthritogenic anti-GPI antibodies (4). The subsequent effector phase of arthritis is predominated by cells of innate immunity, macrophages, and granulocytes, with a paucity of T cells.…”

“…Initiation of arthritis in the K/BxN mouse is attributable to the breakdown of T cell tolerance, with collaboration of autoreactive B cells (3)(4)(5)(6)(7). Arthritis does not develop in the MT mutant mouse, which lacks B cells (6,7).…”

“…In the initial H-2 b background, these mice had no autoimmune phenotype. Remarkably, when the KRN-transgenic mouse was bred to the NOD mouse, all of the F 1 offspring (referred to as K/BxN) spontaneously developed a joint-specific, autoimmune, inflammatory synovitis at age 3-5 weeks (3)(4)(5), which faithfully mimicked many clinical, pathologic, and immunologic features of RA. Cartilage destruction and bone erosion occur in the later stages of the disease.…”

“…The target antigen recognized in K/BxN mice was identified as GPI (3)(4)(5) (Table 2). This ubiquitous glycolytic enzyme catalyzes the interconversion of glucose-6-phosphate and fructose-6-phosphate in the second step of glycolysis.…”