Pathologic conditions related to Ig secretion

Defects in immunoglobulin secretion might be at the basis of certain pathologic conditions such as common variable immunodeficiency (acquired hypogammaglobulinemia). In this disease, the number of membrane Ig-expressing B cells is normal but very little antibody is present in the serum: defects in 7 chain glycosylation have been reported, but their pathogenic relevance remains to be established.

Immunodeficiency with hyper IgM is characterized by high levels of serum IgM and virtual absence of IgG and IgA. In these patients, mutations in the CD40 ligand perturb T cell-B cell interactions, resulting in impaired isotype switching and affinity maturation. Although it is worth recalling that considerable amounts of monomeric IgM are present in the serum of these patients, the significance of this observation is at present unclear.

Many observations on myelomas and heavy chain disease related to defects in or unbalanced Ig secretion have already been mentioned. Secretion of free L chains (Bence Jones proteins), does not appear to be a characteristic of neoplastic plasma cells, but probably reflects an important feature of the Ig assembly line, where the limiting factor is the heavy chain. While cells producing only L are frequent, myeloma mutants producing only H are exceedingly rare, an observation which led to the proposal of heavy chain toxicity. Assembly of complete Ig molecules requires an equal number of L and H chains. Although it might be thought more economical for the cell to synthesize equimolar amounts of the two chains, L chains are produced in excess to optimize HL assembly. The excess L chains can be secreted mainly as L2 homodimers.

Mott cells are plasma cells defective in Ig secretion found in multiple myeloma and certain chronic inflammatory and autoimmune conditions. Mott cells are characterized by cytoplasmic inclusions normally containing immunoglobulin molecules, called Russell bodies, and representing dilated cisternae of the ER. Mott hybridomas have been obtained by fusing splenocytes from NZB mice, a strain highly susceptible to autoimmune diseases. Since these hybridomas express several membrane antigens, a general defect in the secretory pathway may be excluded. That the Mott cell phenotype is due to mutations in the Ig chains is indicated by the observation that Russell bodies are formed upon transfec-tion of certain mutated heavy chains into myeloma cells. Not all nonsecretable chains induced the Mott phenotype. Thus, Russell bodies probably reflect the presence of nontransportable molecules resistant to pre-Golgi degradation.

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