The development of B lineage cells from haematopoietic stem cells in the bone marrow to mature antibody-secreting plasma cells in peripheral lymphoid tissues is a complex and tightly regulated process. The proliferation and maturation of these cells occurs in response to numerous signals from the bone marrow microenvironment, soluble cytokines, interaction with antigen and T lymphocytes and the expression of specific gene products. Lymphocyte development, in both T and B lineages, begins with the commitment of multipotent progenitors to the lymphoid lineage. It is likely that these early stages are in part dependent upon extracellular and stromal signals, though the exact mechanisms of early lymphoid commitment are not well defined. The transcription factor Ikaros appears to play an important role in these initial stages, since mice with targeted deletions of the Ikaros gene lack T, B and natural killer cell development [1]. By contrast, the transcription factors E2A and EBF appear to be more B cell-specific, in that mice that are unable to express these genes have normal numbers of T cells and myeloid cells but few if any B lineage cells [2–4]. The earliest stages of normal B cell development are antigen-independent and occur in the bone marrow in response to stromal cell contact and cytokines. From the pre-B cell stage onwards, B cell development is dependent upon the successful assembly, and functional signalling through, pre-B and B cell receptor complexes. Central to this process is expression of the individual components of the receptor and also the molecules that transduce signals from the receptor to initiate cellular events. This is diagrammatically represented in Fig. 1. The understanding of this highly organized developmental pathway comes not only from in vitro data and the generation of transgenic mice but also from the study of naturally occurring human gene abnormalities. In this review we will outline the major gene defects that result in early B lymphocyte maturation arrest and detail the clinical manifestations and the molecular pathogenesis of these conditions. Considerable emphasis will be devoted to X-linked agammaglobulinaemia (XLA), since this is the most common abnormality of B cell development. Fig. 1 The stages of B lymphocyte development in the bone marrow and periphery are outlined. The most significant B cell developmental block most commonly seen in individuals with X-linked agammaglobulinaemia (XLA) is shown by a dashed line at the pro B cell ... X-linked agammaglobulinaemia Clinical manifestations XLA was the first human immunodeficiency described for which the clinical and laboratory findings dictated effective therapy. In 1952 Bruton reported the case of an 8-year-old boy who had suffered from recurrent infections and in whom analysis of serum by protein electrophoresis revealed no demonstrable gammaglobulin fraction [5]. The boy was treated with monthly intramuscular injections of human gamma globulin with significant clinical improvement. Although there was no family history in this initial case, subsequent cases revealed a similar clinical phenotype with an X-linked pedigree [6,7]. The phenotype of XLA is characterized in its classical form by the almost complete absence of immunoglobulin of all isotypes and the profound reduction of B lymphocytes in the peripheral cir‐culation. As a result the majority of affected boys are prone to recurrent bacterial infection from the age of approximately 4–12 months following the disappearance of maternal immunoglobulin [8]. However, in a significant number of cases (21% in a survey of 44 patients) onset of infections may occur later at 3–5 years of age [9]. The infections are usually caused by pyogenic bacteria, with Haemophilus influenzae, Staphylococcus aureus, Streptococcus pneumoniae, and Pseudomonas being the most common species [8], although mycoplasmas are a significant cause of arthritis [10,11]. The site of infection varies considerably, with sinusitis, otitis media and lower respiratory tract infections being the most common [8,9]. Resistance to viral infection remains predominantly intact except for a susceptibility to enteroviral infection which most commonly results in chronic meningoencephalitis or poliomyelitis in a significant number of cases [12]. Indeed, the major cause of mortality in the series reported by Hermaszewski & Webster [9] was as a result of enteroviral meningoencephalitis. The incidence of enteroviral disease in current populations of XLA patients appears to be less frequent, a finding which may be a result of improved clinical monitoring of patients and optimal immunoglobulin substitution therapy. The disease has always been considered to be confined to the B lymphocyte compartment; however, up to 25% of patients with XLA have profound neutropenia at the time of diagnosis [13]. This may be due to endotoxaemia following severe infections experienced by these patients, or it may be a reflection of the need for the XLA gene product in myeloid cells in situations of stress.
Read full abstract
Nov 4, 2004
Anja C Roden + 11
Open Access
