Self Reactive B Cells Are Selected Against in Bone Marrow

It is estimated that in the mouse the bone marrow produces about 5 X 107 B cells/day but only 5 X 106 (or about 10%) are actually recruited into the recirculating B-cell pool. This means that 90% of the B cells produced each day die without ever leaving the bone marrow. Some of this loss is attributable to negative selection and subsequent elimination (clonal deletion) of immature B cells that express auto-antibodies against self-antigens in the bone marrow.

It has long been established that the crosslinkage of mIgM on immature B cells, demonstrated experimentally by treating immature B cells with antibody against the ^ constant region, can cause the cells to die by apoptosis within the bone marrow. A similar process is thought to occur in vivo when immature B cells that express self-reactive mIgM bind to self-antigens in the bone marrow. For example, D. A. Nemazee and K. Burki introduced a transgene encoding the heavy and light chains of an IgM antibody specific for K , an H-2k class I MHC molecule, into H-2d and H-2d/k mice (Figure 11-5a,b). Since class I MHC molecules are expressed on the membrane of all nucleated cells, the endogenous H-2k and H-2d class I MHC molecules would be present on bone-marrow stromal cells in the transgenic mice. In the H-2d mice, which do not express Kk, 25%-50% of the mature, peripheral B cells expressed the transgene-encoded anti-Kk both as a membrane antibody and as secreted antibody. In contrast, in the H-2d/k mice, which express Kk, no mature, peripheral B cells expressed the transgene-encoded antibody to H-2k (Table 11-1). These results suggest that there is negative selection against any immature B cells expressing auto-antibodies on their membranes because these antibodies react with self-antigen

TABLE 11-ll Expression of transgene encoding IgM antibody to H-2k class I MHC molecules

EXPRESSION OF TRANSGENE

Experimental animal Number of animals tested As membrane Ab As secreted Ab (^g/ml)

SOURCE: Adapted from D. A. Nemazee and K. Burki, 1989, Nature 337:562.

(a) H-2d/k transgenics

Immature B cells

Immature B cells

Nemazee Burki
No mature B cells express anti-Kk

(b) H-2d transgenics

» 25-50% of mature B cells express anti -Kk

(b) H-2d transgenics

» 25-50% of mature B cells express anti -Kk

Cells Bone Marrow
A few mature B cells with new light chains no longer bind Kk

FIGURE 11-5

Experimental evidence for negative selection (clonal deletion) of self-reactive B cells during maturation in the bone marrow. The presence or absence of mature peripheral B cells expressing a transgene-encoded IgM against the H-2 class I molecule K^was determined in H-2 mice (a) and H-2d mice (b). In the H-2 transgenics, the immature B cells recognized the self-antigen Kk and were deleted by negative selection. In the H-2d transgenics, the immature B cells did not bind to a self-antigen and consequently went on to mature, so that 25%-50% of the splenic B cells expressed the trans-gene-encoded anti-Kk as membrane Ig. More detailed analysis of the H-2d/k transgenics revealed a few peripheral B cells that expressed the transgene-encoded ^ chain but a different light chain (c). Apparently, a few immature B cells underwent light-chain editing, so they no longer bound the Kk molecule and consequently escaped negative selection. [Adapted from D. A. Nemazee and K. Burki, 1989, Nature 337: 562; S. L Tiegs et al, 1993, JEM 177:1009.]

(e.g., the Kk molecule in H-2d/k transgenics) present on stromal cells, leading to crosslinking of the antibodies and subsequent death of the immature B cells.

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