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Sequentially along B cell differentiation, the different classes of membrane Ig heavy chains associate with the Ig[alpha]/Ig[beta] heterodimer within the B cell receptor (BCR). Whether each Ig class conveys specific signals adapted to the corresponding differentiation stage remains debated. We investigated the impact of the forced expression of an IgA-class receptor throughout murine B cell differentiation by knocking in the human C[alpha] Ig gene in place of the S[mu] region. Despite expression of a functional BCR, homozygous mutant mice showed a partial developmental blockade at the pro-B/pre-BI and large pre-BII cell stages, with decreased numbers of small pre-BII cells. Beyond this stage, peripheral B cell compartments of reduced size developed and allowed specific antibody responses, whereas mature cells showed constitutive activation and a strong commitment to plasma cell differentiation. Secreted IgA correctly assembled into polymers, associated with the murine J chain, and was transported into secretions. In heterozygous mutants, cells expressing the IgA allele competed poorly with those expressing IgM from the wild-type allele and were almost undetectable among peripheral B lymphocytes, notably in gut-associated lymphoid tissues. Our data indicate that the IgM BCR is more efficient in driving early B cell education and in mucosal site targeting, whereas the IgA BCR appears particularly suited to promoting activation and differentiation of effector plasma cells. B cell receptor | differentiation | immunoglobulin A www.pnas.org/cgi/doi/10.1073/pnas.0912393107

Random V(D)J junctions would generate nonfunctional and/or out-of-frame sequences in about two-thirds of cases and result in abundant transcripts encoding truncated proteins. Although allelic exclusion at the DNA recombination level ensures that a single allele is functional, the frequent biallelic rearrangements need additional mechanisms to down-regulate aberrant transcripts in those cells with both a functionally and a nonfunctionally rear-ranged allele. The process of nonsense-mediated decay targets aberrantly rearranged Ig heavy-chain transcripts, but the situation of light-chain mRNAs is more complex, because they do not meet the usual requirements for nonsense-mediated decay and most often lack a spliceable intron downstream of the premature termination. We studied immunoglobulin heavy-chain -/- pro-B cells in which light chain genes get rearranged and expressed in the absence of any selection for the assembly of a functional B cell receptor. Using this model, we show that the whole [kappa] locus is accessible in pro-B cells and allows the assembly of a broad spectrum of [V.sub.[kappa]][J.sub.[kappa]] segments, most of which are out-of-frame. This model provides an evaluation of the in vivo efficiency of RNA surveillance toward aberrant [kappa] mRNAs produced in pro-B cells. Our data show that nonfunctional [kappa] transcripts are excluded from the mature mRNA pool not only by detecting termination in an upstream exon but also by detecting changes in the position of termination within the last exon. Similar mechanisms efficiently down-regulate nonfunctional [kappa] transcripts arising in normal mature B cells due to the biallelic transcription of rearranged [kappa] genes.

Abstract Definition of the disease AL amyloidosis results from extra-cellular deposition of fibril-forming monoclonal immunoglobulin (Ig) light chains (LC) (most commonly of lambda isotype) usually secreted by a small plasma cell clone. Most patients have evidence of isolated monoclonal gammopathy or smoldering myeloma, and the occurrence of AL amyloidosis in patients with symptomatic multiple myeloma or other B-cell lymphoproliferative disorders is unusual. The key event in the development of AL amyloidosis is the change in the secondary or tertiary structure of an abnormal monoclonal LC, which results in instable conformation. This conformational change is responsible for abnormal folding of the LC, rich in β leaves, which assemble into monomers that stack together to form amyloid fibrils. Epidemiology AL amyloidosis is the most common type of systemic amyloidois in developed countries with an estimated incidence of 9 cases/million inhabitant/year. The average age of diagnosed patients is 65 years and less than 10% of patients are under 50. Clinical description The clinical presentation is protean, because of the wide number of tissues or organs that may be affected. The most common presenting symptoms are asthenia and dyspnoea, which are poorly specific and may account for delayed diagnosis. Renal manifestations are the most frequent, affecting two thirds of patients at presentation. They are characterized by heavy proteinuria, with nephrotic syndrome and impaired renal function in half of the patients. Heart involvement, which is present at diagnosis in more than 50% of patients, leading to restrictive cardiopathy, is the most serious complication and engages prognosis. Diagnostic methods The diagnosis relies on pathological examination of an involved site showing Congo red-positive amyloid deposits, with typical apple-green birefringence under polarized light, that stain positive with an anti-LC antibody by immunohistochemistry and/or immunofluorescence. Due to the systemic nature of the disease, non-invasive biopsies such as abdominal fat aspiration should be considered before taking biopsies from involved organs, in order to reduce the risk of bleeding complications. Differential diagnosis Systemic AL amyloidosis should be distinguished from other diseases related to deposition of monoclonal LC, and from other forms of systemic amyloidosis. When pathological studies have failed to identify the nature of amyloid deposits, genetic studies should be performed to diagnose hereditary amyloidosis. Management Treatment of AL amyloidosis is based on chemotherapy, aimed at controlling the underlying plasma clone that produces amyloidogenic LC. The hematological response should be carefully checked by serial measurements of serum free LC. The association of an alkylating agent with high-dose dexamethasone has proven to be effective in two thirds of patients and is considered as the current reference treatment. New agents used in the treatment of multiple myeloma are under investigation and appear to increase hematological response rates. Symptomatic measures and supportive care is necessary in patients with organ failure. Noticeably, usual treatments for cardiac failure (i.e. calcium inhibitors, β-blockers, angiotensin converting enzyme inhibitors) are inefficient or even dangerous in patients with amyloid heart disease, that should be managed using diuretics. Amiodarone and pace maker implantation should be considered in patients with rhythm or conduction abnormalities. In selected cases, heart and kidney transplantation may be associated with prolonged patient and graft survival. Prognosis Survival in AL amyloidosis depends on the spectrum of organ involvement (amyloid heart disease being the main prognosis factor), the severity of individual organs involved and haematological response to treatment.