Mauno Vihinen¹, Pekka T. Mattsson^2,3 and C. I. Edvard Smith²

¹Department of Biosciences, Division of Biochemistry, P. O. Box 56, FIN-00014 University of Helsinki, Finland

²Center for BioTechnology, Department of Bioscience at Novum, Karolinska Institute, S-141 57 Huddinge and Department of Immunology, Microbiology, Pathology and Infectious Diseases (IMPI), Karolinska Institute, Huddinge University Hospital, S-141 86 Huddinge, Sweden

³Department of Biochemistry and Food Chemistry, University of Turku, Vatselankatu 2, Arcanum, FIN-20014 Turku, Finland

Received 11/24/96; Accepted 12/16/96; On-line 01/01/97

2. INTRODUCTION

X-linked agammaglobulinemia (XLA) is a human immunodeficiency disorder which is caused by a B lymphocyte differentiation arrest affecting the transition of B cell progenitors into mature B lymphocytes. The disease afflicts about 1/200,000 individuals (1). XLA is frequently recognized as the prototype of primary immunodeficiency (PID) (2) and was the first human immune disorder in which an underlying defect - the absence of gammaglobulins - was clearly identified (3). XLA is characterized by an increased susceptibility to infections, mainly those caused by extracellular bacteria (1, 4). In affected individuals, enteroviral infections frequently run a severe course and often resist therapy (1, 4, 5). Using two different approaches, the gene affected in XLA was simultaneously isolated by two groups and found to encode a novel cytoplasmic (non-receptor) tyrosine kinase designated Bruton's agammaglobulinemia tyrosine kinase, Btk (6, 7).

As reviewed in great detail (1, 8), the analysis of serum using electrophoresis, which had only recently been applied in a clinical setting, revealed the absence of detectable immunoglobulins and prompted Bruton to initiate substitution therapy with gammaglobulins.

The increased susceptibility, mainly to bacterial infections in XLA, most often begins during the first year of life when the transferred maternal Ig has been catabolized. There is a pronounced decrease in Ig levels of all isotypes and a virtual absence of humoral response to recall antigens. B lymphocyte and plasma cell numbers are decreased, whereas T lymphocyte subsets are normal and may show a relative increase. The defect is caused by a differentiation arrest confined to the B cell lineage (Fig. 1), distinguishing XLA from several other Ig deficiencies. B lineage cells in all organs are affected resulting in a reduced size of secondary lymphoid organs such as lymph nodes and tonsils.

Figure 1. Schematic representation of B lymphocyte differentiation pathway and the differentiation block/growth arrest in XLA. The pink line represents a partial block and the red line an almost total block in B lineage differentiation in XLA.