Pierre Aucouturier

Human MSH6 Deficiency Is Associated with Impaired Antibody Maturation

Ig class-switch recombination (Ig-CSR) deficiencies are rare primary immunodeficiencies characterized by defective switched isotype (IgG/IgA/IgE) production. Depending on the molecular defect, defective Ig-CSR may also be associated with impaired somatic hypermutation (SHM) of the Ig V regions. Although the mechanisms underlying Ig-CSR and SHM in humans have been revealed (at least in part) by studying natural mutants, the role of mismatch repair in this process has not been fully elucidated. We studied in vivo and in vitro Ab maturation in eight MSH6-deficient patients. The skewed SHM pattern strongly suggests that MSH6 is involved in the human SHM process. Ig-CSR was found to be partially defective in vivo and markedly impaired in vitro. The resolution of γH2AX foci following irradiation of MSH6-deficient B cell lines was also found to be impaired. These data suggest that in human CSR, MSH6 is involved in both the induction and repair of DNA double-strand breaks in switch regions.

Unravelling the immunopathological mechanisms of heavy chain deposition disease with implications for clinical management.

Randall-type heavy chain deposition disease (HCDD) is a rare disorder characterized by tissue deposition of a truncated monoclonal immunoglobulin heavy chain lacking the first constant domain. Pathophysiological mechanisms are unclear and management remains to be defined. Here we retrospectively studied 15 patients with biopsy-proven HCDD of whom 14 presented with stage 3 or higher chronic kidney disease, with nephrotic syndrome in 9. Renal lesions were characterized by nodular glomerulosclerosis, with linear peritubular and glomerular deposits of γ-heavy chain in 12 patients or α-heavy chain in 3 patients, without concurrent light chain staining. Only 2xa0patients had symptomatic myeloma. By serum protein electrophoresis/immunofixation, 13 patients had detectable monoclonal gammopathy. However, none of these techniques allowed detection of the nephrotoxic truncated heavy chain, which was achieved by immunoblot and/or bone marrow heavy chain sequencing in 14 of 15xa0patients. Serum-free kappa to lambda light chain ratioxa0wasxa0abnormal in 11 of 11 patients so examined. Immunofluorescence studies of bone marrow plasma cells showed coexpression of the pathogenic heavy chain with light chain matching the abnormal serum-free light chain in all 3 tested patients. Heavy chain sequencing showed first constant domain deletion in 11 of 11 patients, with high isoelectric point values of the variable domain in 10 of 11xa0patients. All patients received chemotherapy, includingxa0bortezomib in 10 cases. Renal parameters improved in 11xa0patients who achieved a hematological response, as assessed by normalization of the free light chain ratio inxa08xa0cases. Tissue deposition in HCDD relates to physicochemical peculiarities of both variable and constant heavy chain domains. Early diagnosis and treatment with bortezomib-based combinations appear important to preserve renal prognosis. Thus, monitoring of serum-free light chain is an indirect but useful method to evaluate the hematological response.

Immunotherapy in Alzheimer’s Disease: Do We Have All the Pieces of the Puzzle?

Results of Phase III studies involving a large number of Alzheimers disease (AD) patients treated by passive immunotherapy with humanized anti-amyloid β monoclonal antibodies have recently been released. These approaches failed to show a significant clinical benefit in patients with mild to moderate AD. The most considered explanation is that the patients have been treated too late. Whereas targeting patients at asymptomatic stages of the disease is a critical step in the goal of improving the efficacy of such antibody-based strategies, several other important factors should be considered in the development and clinical evaluation of anti-amyloid β immunotherapies, including the as yet poorly understood relationship of AD with the immune system and the importance of cerebral amyloid angiopathy. Better understanding the role of immune responses in AD and their impact on immunotherapy appears essential in the design of alternative or combinatorial immunotherapy approaches in AD, which may imply effectors other than antibodies and even additional antigenic targets.

Impaired Lysosomal Function Underlies Monoclonal Light Chain–Associated Renal Fanconi Syndrome

Monoclonal gammopathies are frequently complicated by kidney lesions that increase the disease morbidity and mortality. In particular, abnormal Ig free light chains (LCs) may accumulate within epithelial cells, causing proximal tubule (PT) dysfunction and renal Fanconi syndrome (RFS). To investigate the mechanisms linking LC accumulation and PT dysfunction, we used transgenic mice overexpressing human control or RFS-associated κLCs (RFS-κLCs) and primary cultures of mouse PT cells exposed to low doses of corresponding human κLCs (25 μg/ml). Before the onset of renal failure, mice overexpressing RFS-κLCs showed PT dysfunction related to loss of apical transporters and receptors and increased PT cell proliferation rates associated with lysosomal accumulation of κLCs. Exposure of PT cells to RFS-κLCs resulted in κLC accumulation within enlarged and dysfunctional lysosomes, alteration of cellular dynamics, defective proteolysis and hydrolase maturation, and impaired lysosomal acidification. These changes were specific to the RFS-κLC variable (V) sequence, because they did not occur with control LCs or the same RFS-κLC carrying a single substitution (Ala30→Ser) in the V domain. The lysosomal alterations induced by RFS-κLCs were reflected in increased cell proliferation, decreased apical expression of endocytic receptors, and defective endocytosis. These results reveal that specific κLCs accumulate within lysosomes, altering lysosome dynamics and proteolytic function through defective acidification, thereby causing dedifferentiation and loss of reabsorptive capacity of PT cells. The characterization of these early events, which are similar to those encountered in congenital lysosomal disorders, provides a basis for the reported differential LC toxicity and new perspectives on LC-induced RFS.

Ig-Related Renal Disease in Lymphoplasmacytic Disorders: An Update

Ig-related renal diseases occurring in lymphoplasmacytic disorders (LPD) cover a wide spectrum of renal lesions. Except for cast nephropathy, which is almost specific for multiple myeloma, similar renal lesions caused by deposition or precipitation of monoclonal Ig-related material may occur in the various types of LPD. Because the secreted Ig provides the link between the LPD and the kidney disease, the renal outcome is linked to efficacy of chemotherapy. In the past 10 years, considerable advances have occurred in chemotherapy regimens with the advent of new classes of drugs, which already result in markedly improved renal and vital survival.

Complete remission of monoclonal gammopathy with ocular and periorbital crystal storing histiocytosis and Fanconi syndrome

A 62-year-old woman presented with crystalline keratopathy, crystal-storing histiocytosis, Fanconi syndrome, and a serum monoclonal IgG-κ and urinary κ light chain. Histology and electron microscopy studies revealed the presence of crystals within macrophages in multiple eye sites, in the kidney and in the bone marrow. The variable domain of the pathogenic κ light chain related to the Vk1-39 gene that was also involved in most previously reported cases of Fanconi syndrome. Owing to the severity of the damage to the eye and a potentially poor kidney prognosis, the patient underwent autologous stem cell transplantation. After 18 months follow-up, she is in complete hematological, ophthalmological, and renal remission.

Impaired long-term immune protection following pneumococcal 13-valent/23-valent polysaccharide vaccine in systemic lupus erythematosus (SLE)

Although patients with systemic lupus erythematosus (SLE) are at increased risk for Streptococcus pneumoniae infection,1 2 vaccination coverage remains dramatically low in SLE,3 and efficacy of the now recommended prime-and-boost strategy using 13-valent pneumococcal conjugate vaccine (PCV13) and 23-valent pneumococcal polysaccharide vaccine (PPSV23) is not known.nnConsecutive patients with SLE admitted in our daycare hospital unit were prospectively enrolled to receive PCV13 followed by PPSV23 8 weeks later. Immune protection, defined by an antigen-specific IgG concentrationxa0≥1.3u2009µg/mL for at least 70% of seven pneumococcal serotypes (4, 6B, 9V, 14, 18C, 19Fxa0and 23F), was assessed at baseline, 2 and 12 months. Patients were defined as ‘long-term protected (LTP)’ when seroconversion was observed 2 months and 12 months after PCV13 shot. Patients were considered ‘short-term protected (STP)’ when seroconversion was observed 2 months but no more at 12 months after PCV13 shot. Patients were ‘not protected (NP)’ when seroconversion occurred neither 2 months nor 12 months after PCV13 shot. Laboratory tests included the analysis of blood …