Case Presentation
The case presentation follows a 27-year-old male patient with end-stage renal disease secondary to X-linked Alport syndrome. After three years on hemodialysis, he received a deceased donor kidney transplant. Post-transplant, the patient initially presented with stable creatinine levels of around 1.2 mg/dL. At 10 months post-transplant, he developed an acute onset of hematuria, proteinuria and rapidly deteriorating allograft function, with a creatinine level rising to 4.6 mg/dL over one week.
Dysmorphic red blood cells (RBCs) and RBC casts were detected by urinalysis. Allograft biopsy revealed linear deposition of immunoglobulin G along the GBM. Crescent formation presented in 60% of the glomeruli along with high titer circulating anti-GBM antibodies.
The findings confirmed the diagnosis of de novo anti-GBM disease in a kidney allograft, but the rheumatology team mulled the immunopathology of the case.
“The development of two rare, and seemingly unrelated, kidney diseases in one patient raises interesting questions pertinent to the pathogenesis of humoral autoimmunity,” write Dr. Jackson and Dr. Ponnan.
Layered Checkpoints in B Cell Tolerance
Central tolerance eliminates most highly autoreactive B cells, but B cell tolerance is maintained in the periphery.
Central tolerance occurs in the bone marrow. It comprises clonal deletion of high-affinity self-reactive B cells and receptor editing of these cells to modify B cell receptor binding. During peripheral tolerance, self-reactive mature B cells become functionally unresponsive to antigens. These anergic B cells also show a reduced ability to access B cell follicles in secondary lymphoid organs and have short lifespans.
“These anergic B cells could potentially become activated and enter a germinal center response if they successfully acquire T cell help,” the authors explain. “For this reason, a key peripheral tolerance checkpoint limits the recruitment of self-reactive B cells into germinal centers during initial cognate interactions between T helpers and B cells.”
During germinal center tolerance, de novo autoreactive B cells generated by somatic hypermutation are deleted. B cell tolerance is also regulated by T cells via the central deletion of potential B cell helpers and the control of germinal center responses, influenced by the balance of T follicular helper and regulatory cells.
Despite the potential for autoreactive B cells to escape inhibitory control, the immune system maintains cells with low self-antigen affinity in a functional anergy state. The authors explain the reason for this is that “many pathogens express surface epitopes that mimic self-antigens,” so “a repertoire entirely devoid of self-reactivity would leave ‘gaps’ in immune coverage rendering individuals vulnerable to invasive pathogens.”