Page 835 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 51 Congenital Disorders of Lymphocyte Function 721

Activated BAFF
T cell (60-mer)
T cell,
↑IL-4, IL-10 APRIL B cell,
Syndecan-2 BAFF or DC

CD70
ICOS Ag

CD81 CD21
Igβ
ICOS-L Igα HSPG TACI BAFF-R BCMA CD27
CD19
Activated B Naive B PC

Differentiation
Survival-apoptosis Survival Survival Survival
Inhibition
Ig production
TI-2 responses
Fig. 51.3 GENETIC DEFECTS ASSOCIATED WITH COMMON VARIABLE IMMUNODEFI-
CIENCY. Schematic of cell surface molecules expressed on B cells and their ligands, highlighting those in
which defects have been shown to be associated with CVID. Ag, Antigen; APRIL, a proliferation-inducing
ligand; BAFF, B-cell–activating factor; BAFFR, B-cell–activating factor receptor; BCMA, B-cell–maturation
antigen; DC, dendritic cell; HSPG, heparin sulfate proteoglycan; ICOS, inducible T-cell costimulator; ICOS-L,
inducible T-cell costimulator ligand; Ig, immunoglobulin; IL-4, interleukin 4; IL-10, interleukin 10;
PC, plasma cell; TACI, transmembrane activator and calcium modulator and cyclophilin ligand interactor;
TI-2, T-cell–independent type 2.

“variable” nature of the clinical manifestations of CVID patients Other autoimmune complications include rheumatoid arthritis,
could reflect genetic heterogeneity, but also refers to distinct clinical systemic lupus erythematosus, hypothyroidism, vitiligo, psoriasis,
and immunological features that distinguish subgroups of CVID diabetes, and autoimmune gastritis with pernicious anemia. Poly-
patients. However, the most common genetic variant described to clonal lymphocytic granulomatous infiltrates are common and may
date (mutations in transmembrane activator and calcium modulator involve the lungs, liver, or gut (causing enteropathy that is resistant
and cyclophilin ligand interactor [TACI]) can be found in asymp- to gluten withdrawal). Finally, both lymphoid (non-Hodgkin lym-
tomatic individuals, and more likely represents a predisposition to phoma, chronic lymphocytic leukemia) and nonlymphoid (gastric
CVIDs than primary cause. Thus, the genetic causes of the majority cancer) malignancies are more frequent in CVID, although the latter
of cases of CVIDs remain obscure and are not clearly monogenic in may be related to Helicobacter pylori infection.
nature. Replacement of immunoglobulins and treatment and prevention
Diagnostic criteria for CVIDs were established in 1999 by con- of infection remains the mainstay of management of CVID. Immu-
sensus of European and Pan-American societies, and include the nosuppression may be needed for inflammatory and autoimmune
presence of hypogammaglobulinemia (<2 standard deviations below manifestations. Disease manifestations such as autoimmunity, poly-
the mean for age of IgG, IgA, and/or IgM) and the lack of specific clonal lymphocytic infiltrative disease, enteropathy, and malignancy
antibody responses in individuals with onset of symptoms >2 years have differential and increasing impact on survival (relative risk of
of age, for whom other causes of humoral immunodeficiency have death 2.5, 3.0, 4.0, and 5.5, respectively), while patients with solely
been ruled out. The number of circulating B cells detected is variable. infectious manifestations have equivalent survival to the general
Specific antibody responses should be assessed for more than one population. Treatment with HCT has been performed with limited
antigen. Because an increasing number of gene defects causing success, and often in the context of consolidative treatment for
hypogammaglobulinemia early in life have been identified, many lymphoproliferation.
experts would recommend limiting the diagnosis of CVID to patients Immunophenotyping, genotyping, and recently genome-wide
in whom symptoms appeared at >4 years of age. association studies have been performed in an attempt to subcatego-
Consistent with the antibody deficiency, CVID patients have rize the heterogeneous group of CVIDs into pathobiologically relevant
recurrent bacterial infections of the respiratory tract, sepsis with groups. In large part the associations have not been sufficiently robust
encapsulated organisms, and infections from Ureaplasma uraelyticum, to direct diagnosis or clinical management, and underscore the
Giardia species and enteroviruses. However, variable derangement of genetic heterogeneity of the disease. B-cell subphenotypes most
T-cell numbers and function often results in noninfectious manifesta- common among CVID patients include a severe reduction in
+
+
–
tions, including autoimmunity, lymphoid infiltration or proliferation, switched memory B cells (CD19 CD27 IgD ); some patients mani-
+
hi
hi
and malignancy. In one survey only 26% of CVID patients had fest expansion of transitional B cells (CD19 CD24 CD38 ), expan-
low
low
infections as the only manifestation of disease. Autoimmune cytope- sion of CD21 CD38 B cells (the latter thought to play a role in
nias are quite common (~12%) and may be the presenting feature. autoimmunity), or reduction in CD4 T-cell number.