G. Touchard

Diffuse small intestinal lymphoid infiltration in nonimmunodeficient adults from Western Europe

In two white adults born, raised, and living in central France and presenting with long-lasting malabsorption, massive and diffuse lymphoid infiltrate of the lamina propria associated with crypt scarcity was found along the whole small bowel. It was mostly composed of mature lymphocytes, focally mixed with plasma cells and reactive germinal centers. There was no evidence of celiac disease, systemic or intestinal immune deficiency or alpha-chain disease, overt lymphoid malignancy, or stagnant-loop syndrome. By immunofluorescence the infiltrate was constituted in 1 case of polyclonal B cells and, in the other, of a large majority of T11, T8, T10, and class II-positive T cells associated with a population of monotypic B cells. A gluten-free diet and parenteral nutrition proved ineffective. A dramatic and protracted clinical response was observed in both patients after the onset of oral tetracycline therapy, and still persists after 8 and 5.5 yr, respectively, together with morphologically unchanged small bowel infiltrate. These cases may be the equivalents, in people from Western developed countries, of the predominantly lymphocytic variety of the immunoproliferative small intestinal disease described in people from developing countries.

Molecular study of an IgG1κ cryoglobulin yielding organized microtubular deposits and glomerulonephritis in the course of chronic lymphocytic leukaemia

Glomerulonephritis with organized microtubular monoclonal immunoglobulin deposits (GOMMID) and glomerulonephritis related to type I cryoglobulin are well‐known but rare complications of B cell derived chronic lymphocytic leukaemia. In these disorders, monoclonal Ig have never been studied at the molecular level. We conducted a pathological and molecular analysis in a patient with chronic lymphocytic leukaemia, glomerulonephritis and a single circulating monoclonal Ig. Unusual IgG1κ kidney deposits were observed. The heavy and light chain variable region sequences of that cryoprecipitating monoclonal Ig were characterized. Light microscopy revealed glomerulonephritis typical of cryoglobulinaemia, with neutrophil and macrophage infiltration, endocapillary hyperplasia and few protein thrombi. Electron microscopic study clearly evidenced numerous subepithelial mixed granular and organized deposits with a unique microtubular organization, reminiscent of the GOMMID. The Ig molecule sequence revealed alterations of charge and hydrophobicity potentially promoting a crystal‐like aggregation and the aggregation of microtubules.This description suggests that common mechanisms are involved in various forms of precipitation and/or deposition of complete Ig molecules, with a variable extent of organization and with a possible overlap between pathological patterns of either glomerulonephritis with microtubular deposits or type I cryoglobulinic glomerulonephritis.

Strategies to model AL amyloidosis in mice.

Monoclonal immunoglobulin (Ig) deposition in AL amyloidosis is a severe complication of lymphoproliferative disorders. Research on this disease suffers from the lack of animal models, as they could allow for the testing of new innovative therapeutic strategies. We are trying to develop a transgenic animal model for this disease by overexpressing Ig light chain (LC) sequences cloned from AL amyloidosis patients. After several unsuccessful attempts using additional transgenesis due to low LC expression, we currently are following a strategy of targeted insertion of human LC sequences in the mouse endogenous kappa LC locus. We describe here the first data from this ‘knock-in’ model and propose future prospects to increase the rates of free LC and mimic the human disease. Absence of amyloid deposits in such models would raise the possibility of a resistance to AL amyloidosis in mice and question the feasibility of a reliable animal model for this disease.