Autoreactive B-1 B cells: Constraints on natural autoantibody B cell antigen receptors

Abstract

B-1 B-cells constitute a distinctive population of cells that are enriched for self-reactive B cell receptors (BCRs). These BCRs are encoded by a restricted set of heavy and light chains, including heavy chains that lack nontemplated nucleotide additions at the V-D and D-J joining regions. One prototype natural autoantibody produced by B-1 B cells binds to a cryptic determinant exposed on senescent red blood cells that includes the phosphatidylcholine (PtC) moiety. The V(H)11Vkappa9 BCR, which accounts for a large fraction of the anti-PtC specificity, is underrepresented in other B-cell populations, including newly formed B cells in bone marrow, and the transitional B cells, follicular B cells, and marginal zone B cells in spleen. Previous work has shown that V(H)11 heavy chains pair ineffectively with surrogate light chain (SLC) and so do not promote development in bone marrow, but instead allow fetal liver maturation because of a fetal preference for weaker pre-BCR signaling. Such inefficient SLC pairing constitutes one constraint on the maturation of B cells containing V(H)11 rearrangements that biases their generation to fetal development. Here, we examine another possible bottleneck to the B1 cell repertoire: light chain pairing with V(H)11 heavy chain, finding very significant preferences.

Checkpoints that control B cell development

“…It has been estimated that more than half of the newly generated antibodies can bind autoantigens (71). More than half of all BI cells appear to be in a stimulated, G1-like stage of the cell cycle; autoreactive and polyreactive antibodies are found in this BI population (72). Such B cells may be more easily activated in autoimmune diseases.…”

The Geo-epidemiology of Temporal (Giant Cell) Arteritis

“…We should note that GCA has a strong correlation with polymyalgia rheumatica (PMR), but this will not be discussed within this manuscript. We will also not discuss either the mechanisms of the immune response or related themes in vasculitis, but rather refer the reader to recent literature on not only polymyalgia rheumatica, but also vasculitis and methodologies used to decipher the etiologies of other rheumatic diseases [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15].…”

The Chemical Pathway to Primary Biliary Cirrhosis

“…This approach will provide clues to the unanswered questions on PBC, and the disease will finally evolve into 'a matter of (well-known) bad genes and bad luck' [44]. There are obviously a variety of generic issues which relate to the mechanisms of loss of tolerance, and we refer to a recent series of articles which deal specifically with the pathophysiology of autoimmune disease [45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60].…”