X-Linked Agammaglobulinemia

Abstract

X-linked agammaglobulinemia (XLA) is a primary immunodeficiency caused by mutations in the gene for Bruton tyrosine kinase (BTK) that result in the deficient development of B lymphocytes and hypogammaglobulinemia. Because the disorder is uncommon, no single institution has had sufficient numbers of patients to develop a comprehensive clinical picture of the disorder. Accordingly, a national registry of United States residents with XLA was established in 1999 to provide an updated clinical view of the disorder in a large cohort of patients. A total of 201 patients were registered by 66 physicians. The estimated birth rate for the 10-year period of 1988-1997 was 1/379,000. Infection was the most common initial clinical presentation (85%), followed by a positive family history (41%) and neutropenia (11%). Although the average age of diagnosis was younger in patients with a positive family history (mean, 2.59 yr) than in patients with a negative family history (mean, 5.37 yr) (p < 0.001), only 34.5% of patients with a positive family history at the time of their birth were diagnosed before clinical symptoms developed-that is, based on family history alone. Seventy percent of patients had at least 1 episode of otitis, 62% at least 1 episode of pneumonia, 60% at least 1 episode of sinusitis, 23% at least 1 episode of chronic/recurrent diarrhea, 21% at least 1 episode of conjunctivitis, 18% at least 1 episode of pyoderma and/or cellulitis, 11% at least 1 episode of meningitis/encephalitis, 10% at least 1 episode of sepsis, 8% at least 1 episode of septic arthritis, 6% at least 1 episode of hepatitis, and 3% at least 1 episode of osteomyelitis. Fourteen of 201 (6.9%) patients were dead at the time they were entered in the Registry. However, in a prospective 4 /4-year follow-up of living patients, only 3/80 (3.75%) patients died. Causes of death included disseminated enterovirus infection (n = 6), pulmonary insufficiency (n = 5), adenovirus infection (n = 1), sepsis (n = 1), acquired immunodeficiency disease syndrome (AIDS) (n = 1), myocarditis (n = 1), hepatitis (n = 2), and stem cell transplantation (n = 1).

Signaling by Toll-like Receptors 8 and 9 Requires Bruton's Tyrosine Kinase

“…In fact, enteroviral infections are the most common cause of mortality in XLA patients (12,28). Additionally, patients with XLA are known to be susceptible to herpes viruses such as HHV-6, varicella-zoster, herpes simplex, and cytomegalovirus (29).…”

“…This suggested a possible role for Btk in TLR8 and TLR9 signaling, although this has never been examined directly. Btk-deficient mice have exhibited high susceptibility to acute mouse adenovirus type-1 (MAV-1) in contrast to controls, and XLA patients are highly susceptible to enteroviral infections, indicating a possible role for Btk in preventing virus-induced disease (11,12). This could be due to a role for Btk in TLR8 or TLR9 signaling.…”

Targets for Ibrutinib Beyond B Cell Malignancies

“…In affected individuals, a defect in B cell maturation and function leads to the profound reduction of serum immunoglobulins and increased susceptibility to infections 38. A less severe, B cell disorder manifested at later stages of B cell development is observed in mice carrying BTK mutations 39, 40.…”

Артрити При Первинних Імунодефіцитах

“…При хворобі Бруто-на (XLA) артрити спостерігаються з різною часто-тою [73]. Асептичний артрит при даному ПІД відміча-ли в 11 % хворих, ЮІА -у 17 % та у 8 % -септичний артрит [24,26]. Септичний артрит у дітей із хворобою Брутона найчастіше пов'язують з мікоплазмою.…”