How I Approach Light Chain Amyloidosis.

Immunoglobulin Light Chain Amyloidosis (AL) is a progressive disease which leads to organ dysfunction and death. Tremendous progress has been made in staging, response, and treatment. The key to better survival though is early diagnosis which can be difficult since the symptoms are often nonspecific and can be seen in more common conditions. Once the diagnosis is confirmed, staging systems are available to provide prognosis on overall and renal survival. There are a number of treatments now available that are effective and well-tolerated. Response criteria have also been developed for hematologic and renal response in order to maximize response and minimize adverse effects. Newer therapies are being developed in particular anti-fibril therapies that are in clinical trials. For those patients who had a very good partial response or better, kidney transplantation may be an option if the kidney failure is not reversed.

Immunoglobulin A nephropathy is characterized by anticommensal humoral immune responses.

IgA nephropathy (IgAN) is a leading cause of kidney failure, yet little is known about the immunopathogenesis of this disease. IgAN is characterized by deposition of IgA in the kidney glomeruli, but the source and stimulus for IgA production are not known. Clinical and experimental data suggest a role for aberrant immune responses to mucosal microbiota in IgAN, and in some countries with high disease prevalence, tonsillectomy is regarded as standard-of-care therapy. To evaluate the relationship between microbiota and mucosal immune responses, we characterized the tonsil microbiota in patients with IgAN versus nonrelated household-matched control group participants and identified increased carriage of the genus Neisseria and elevated Neisseria-targeted serum IgA in IgAN patients. We reverse-translated these findings in experimental IgAN driven by BAFF overexpression in BAFF-transgenic mice rendered susceptible to Neisseria infection by introduction of a humanized CEACAM-1 transgene (B × hC-Tg). Colonization of B × hC-Tg mice with Neisseria yielded augmented levels of systemic Neisseria-specific IgA. Using a custom ELISPOT assay, we discovered anti-Neisseria-specific IgA-secreting cells within the kidneys of these mice. These findings suggest a role for cytokine-driven aberrant mucosal immune responses to oropharyngeal pathobionts, such as Neisseria, in the immunopathogenesis of IgAN. Furthermore, in the presence of excess BAFF, pathobiont-specific IgA can be produced in situ within the kidney.