Abstract
BackgroundImmature bone marrow B cells are known to have longer CDR3 than mature peripheral B cells, and this genetic characteristic has been shown to correlate with autoreactivity in these early cells. B-cell Central tolerance eliminates these cells, but it is known that autoreactive B cells nevertheless appear commonly in healthy human blood. We examined over 7,300 Ig genes from Genbank, including those annotated by their discoverers as associated with autoreactivity, to determine the genetic correlates of autoreactivity in mature B cells.ResultsWe find differential biases in gene segment usage and higher mutation frequency in autoreactivity-associated Ig genes, but the CDR3 lengths do not differ between autoreactive and non-autoreactive Ig genes. The most striking genetic signature of autoreactivity is an increase in the proportion of N-nucleotides relative to germline-encoded nucleotides in CDR3 from autoreactive genes.ConclusionWe hypothesize that peripheral autoreactivity results primarily from somatic mutation, and that the genetic correlates of autoreactivity in mature B-cells are not the same as those for autoreactivity in immature B cells. What is seen in mature autoreactive B cells are the correlates of autoreactive potential, not of autoreactivity per se. The autoreactive potential is higher for V(D)J rearrangements encoded to a large extent by N-nucleotides rather than by the gene segments that, we posit, have been selected in germline evolution for their suppression of autoreactive potential.
Highlights
Immature bone marrow B cells are known to have longer CDR3 than mature peripheral B cells, and this genetic characteristic has been shown to correlate with autoreactivity in these early cells
Gene Segment Usage For the J segments, both the A and NP gene sets showed significant differences compared to every other gene set, as did the rheumatoid arthritis (RA) and P gene sets, except when compared to each other (Figures 1, 2)
The other hypothesis does not depend on leakiness of central B cell tolerance, but instead relies on the generation of autoreactivity by somatic mutations incorporated after primary B cell development
Summary
Immature bone marrow B cells are known to have longer CDR3 than mature peripheral B cells, and this genetic characteristic has been shown to correlate with autoreactivity in these early cells. Functional Ig genes result from the combinatorial joining of gene segments from two (light chain) or three (heavy chain) classes; V (variable), D (diversity), and J (joining) [1,2] This process, known as V(D)J recombination, generates tremendous receptor diversity through the pairing of various gene segments, the selection of the recombination sites at which the segments are joined, and the addition of non-templated nucleotides (n-nucleotides) between adjoining gene segments. The adaptive immune system generates diversity and adapts its antigen receptors via stochastic somatic processes as microbes themselves diversify and adapt through Darwinian evolution With such randomness in the formation of antigen receptor genes, it is inevitable that autoreactivity will arise. Three primary B-cell-specific mechanisms for avoiding Ig-mediated autoimmunity have been identified: selective deletion, anergy and receptor editing [6,7,8,9,10]
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