X-linked immune deficiency (xid) is a sex-linked recessive mutation that originated in the CBA/HN substrain (Amsbaugh et al., 1972). It is now available on many backgrounds. The gene is located between Pgk-1 and Plp on the X chromosome. An xid-linked gene family (Cohen et al., 1985) has subsequently been found to segregate from xid (Mark Davis, Stanford University, Stanford, California, personal communication), and therefore, the family cannot include the xid locus.

PATHOPHYSIOLOGY

Expression of xid results in a marked deficiency in circulating IgM, IgG₃, and l-bearing antibodies (Scher, 1982). Affected animals fail to respond to repeating unit polysaccharide antigens or their haptenated derivatives, i.e., antigens that can elicit a thymus-independent response but that are not polyclonal mitogens (thymus-independent type-2 antigens) (Mosier et al., 1976). Responses to thymus-dependent or thymus-independent type-1 antigens (polyclonal mitogens or their haptenated derivatives) are present, although they may be of lower magnitude than normal. The absolute number of B cells is reduced by one half or more. This is not due to a uniform decrease in all B cells, as identified subpopulations are missing. In particular, neither neonatal splenic CD5⁺ nor adult peritoneal CD5⁺ cells are present (Hayakawa, et al., 1983). The repertoire of expressed antibodies of normal and xid mice differ in that those of xid mice fail to express certain heavy- and light-chain combinations (Kenny et al., 1981). The missing immunoglobulins appear to be those usually seen in responses to determinants of common type-2 thymus-independent antigens, such as the phosphorylcholine of pneumococcal polysaccharide. Early claims of associated T-cell defects have not been verified.

Transfer of normal B cells to xid mice corrects the defect, while B cells transferred from xid mice to normal hosts retain their defective phenotype (Scher et al., 1975), indicating that the problem in xid mice is intrinsic to B cells. B cells from xid mice survive very poorly in vitro, and their in vivo lifespan is somewhat shortened (Sprent and Bruce, 1984a). Furthermore, in the absence of T cells, the differentiation and in vivo survival of B cells and antibody production is severely impaired. Thus, thymectomy of xid mice causes a loss of B cells (Sprent and Bruce, 1984b), and the combined expression of xid and nude (nu) results in athymic mice with a severe deficit of B cells (Wortis et al., 1982; Mond et al., 1982).

In the absence of detailed knowledge of the pathogenesis of xid, two major hypotheses have been advanced. One holds that xid mice lack a distinct lineage of B cells, the lineage defined as exclusively of fetal origin and committed to become CD5⁺ cells (Karagogeos and Wortis, 1987). According to this theory, the missing lineage of B cells is exclusively responsible for antibody production in response to repeating unit, sIg cross-linking, thymus-independent type-2 antigens. The alternative hypothesis holds that all B cells in xid mice are affected and are incapable of maintaining viability in the absence of exogenous support (perhaps interleukins) supplied by T cells. An extension of this second hypothesis is that when B cells in xid mice are stimulated to enter a thymus-independent pathway of antibody production in the absence of extrinsic mitogen (by TI-2 antigen), they fail to survive. Stimulation by alternative mechanisms (mitogenic thymus-independent type-1 antigens or cognate interaction with T-helper cells) permits cell survival. Evidence for the second hypothesis is that unlike normal adult B cells, cells from xid mice undergo very little proliferation in response to sIg cross-linking by anti-immunoglobulin. Additional evidence is that there is impaired maturation of B cells in the adult bone marrow of athymic xid mice (i.e., nu xid) (Karagogeos et al., 1986), an indication that all B cells are affected.

The failure of B cells from xid mice to express certain heavy-light chain combinations is known to be caused by post-rearrangement deletion because these B cells can be found in the marrow but not in the periphery (Klinman and Stone, 1983). The same phenomenon is seen in exaggerated form in xid mice carrying a transgene for an immunoglobulin (M167, a mk combination specific for phosphoryl-choline) not normally seen in xid mice (Kenny et al 1991). In this experimental model, B cells expressing the transgene are found in the bone marrow but not in the periphery. The missing B cells in this model are autoreactive, and a loss of autoreactive B cells appears to be characteristic of all xid mice. For example, the neonatal splenic and adult peritoneal CD5⁺ populations contain a high frequency of cells that produce natural autoantibodies. This repertoire deletion mechanism has an interesting effect when xid is expressed in combination with various genes that confer a predisposition to polyreactive systemic autoimmune diseases (e.g., viable motheaten (me^v, (Scribner et al., 1987) or the genes unique to BXSB (Steinberg et al., 1987) and NZB mice (Nakajima et al. 1979). The result is a marked decrease in autoantibody production and prolongation of life.

The biochemical defect in xid mice has not been identified. There is evidence suggesting that there are defects in the transmembrane IgM complex (Chen et al., 1990), as well as alterations in transmembrane signaling via the complex (Rigley et al., 1989). Alternative models arise from evidence that B cells from xid mice fail to respond to an interleukin (IL-10) that is produced by both T-helper-2 cells and B cells (Go et al., 1990). Here the theory is that defective B cells fail to respond to (and may not produce) an autocrine factor necessary for their survival in the absence of T-cell factors.

HUSBANDRY

Affected mice do well under standard barrier conditions, and special precautions are generally not needed. However, these mice are known to be extremely susceptible to certain bacterial infections (Duran and Metcalf, 1987).

REPRODUCTION

These animals breed normally and can be maintained by brother X sister matings. Crosses between homozygous females and normal males produce X^xidY males that are affected and X^xidX females that are not. In fact, because of X chromosomal inactivation, these F₁ females are chimeras with a population of B cells composed of a majority of normal (maternal X inactivated) and a few affected (paternal X inactivated) B cells (Nahm et al., 1983). For experimental purposes, the ideal control animals are obtained by reciprocal crosses of CBA/N mice with an unaffected strain, resulting in the production of affected X^xidY and unaffected XY F₁ males. This strategy avoids differences caused by background genes when strains are compared or to sex-related differences that complicate comparisons of X^xidY and X^xid F1 mice.

REFERENCES

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