Page 502 - Clinical Immunology_ Principles and Practice ( PDFDrive )

482 PARt fouR Immunological Deficiencies

varying block in B-cell maturation. Careful analysis of B cells which is unique for BAFF, is expressed on B cells and on resting
in patients has also revealed a spectrum of immune deficiency T cells. The BAFF/APRIL system plays a key role in mature
ranging from the nearly complete absence of memory B cells to B-cell homeostasis and development. BAFF and APRIL can also
a less severe disorder. All of these findings serve to underline induce class switching in naïve human B cells. Loss-of-function
the complex etiology for the disorder, and many details remain (autosomal recessive) or altered-function (autosomal dominant)
to be elucidated. The MHC represents the most common genetic TACI alleles have been found in approximately 10% of patients
22
31
susceptibility locus for CVID. Because of linkage disequilibrium, with CVID in many series. Two polymorphic alleles, A181E
the gene, or genes, within this locus that create susceptibility and C104R, are prominent in patients with CVID who have
have yet to be identified with certainty. Non–MHC-associated TACI alterations. These alleles are also present in approximately
single-gene defects have been identified, although they represent 2% of the normal population, suggesting that the presence of
only a minority of patients with CVID. These include function-loss these altered alleles functions as a susceptibility factor for the
mutations in genes involved in late-stage B cell–T cell communica- development of the disease. Family members may have IgA
tion, late-stage B-cell growth factors, and B-cell and T-cell signal- deficiency or may have no evidence of immune dysfunction.
ing and activation pathways (see Table 34.1). These include the However, patients with CVID who have these altered alleles have
genes for ICOS (CVID1), an immune costimulator molecule a higher prevalence of complications from CVID, including lym-
32
used by T cells to activate B cells in germinal centers; BAFFR phoproliferation, splenomegaly, and autoimmune phenomena.
(CVID4) and TACI (CVID2), the receptors for BAFF, CD19 BAFF-R deficiency has been reported in four patients with CVID
(CVID3), CD21 (CVID7), and CD81 (CVID6), components of to date. 30
the B-cell costimulatory receptor; CD20 (CVID5), an important
marker of B-cell differentiation; and LRBA, Cytotoxic T lym- CD20 (CVID5)
phocyte antigen-4 (CTLA-4), PKCδ, Tweak, PIK3CD, PIK3R1, CD20 encodes a B-cell membrane–spanning molecule important
NF-κB2, and KMT2D, which are involved in B-cell and T-cell in B-cell proliferation and differentiation. It is expressed from
signaling pathways. TLR7 and TLR9 activation can be deficient early pre-B until mature B-cell stage but is lost on differentiation
in these patients, although the genes are intact. 27 to plasma cell. One case of a female consanguineous patient
with CD20 deficiency with low IgG and normal IgA and IgM
The Major Histocompatibility Complex levels and impaired antibody responses to pneumococcal polysac-
A large array of genes that play important roles in the control of charides, has been reported. 30,33
the immune response are located in the MHC on chromosome 6
(Chapter 5). Studies at the University of Alabama at Birmingham ICOS (CVID1)
have shown that in the Southeastern United States the majority ICOS is a T-cell surface receptor that is important for germinal
of patients with IgAD and CVID share parts or all of one of center formation, terminal B-cell differentiation, effector T-cell
three extended MHC haplotypes marked by either HLA-DQ2, responses, and immune tolerance. Patients with ICOS deficiency
-DR17(3), and -B8 or HLA-DQ2, -DR7, and -B44. The combined have low to absent B cells, and some have varying degrees of
results of three studies of patients from Alabama, New England, defective T-cell signaling. They present with recurrent respiratory
and Australia indicated a 13% prevalence of immunodeficiency in tract infections and autoimmune complications. 30,33
individuals homozygous for HLA-DQ2, -DR17(3), and -B8. These
MHC alleles are also more common in patients who suffer from The LRBA (Cvid8)–CTLA-4 Axis
diabetes mellitus, pernicious anemia, celiac disease, autoimmune Lipopolysaccharide-responsive beige-like anchor protein (LRBA)
thyroid disease, and myasthenia gravis. Some individuals with is a cytosolic protein that functions in vesicle trafficking,
TACI mutations inherited MHC haplotypes associated with autophagy, and cell survival. It is expressed by almost all cell
28
the disease, and the combination of specific MHC and KIR types with higher expression in immune effector cells. CTLA-4
29
alleles also increases susceptibility. This suggests that epistatic is an inhibitory T-cell receptor (TCR) that competes with the
interactions between different susceptibility alleles may influence costimulatory protein CD28 for binding CD80/86, thereby
the penetrance of the disorder. preventing excessive T-cell activation and maintaining immune
tolerance. LRBA plays a role in CTLA-4 surface expression.
The CD19 (CVID3), CD81 (CVID6), CD21 (CVID7) B-Cell Patients with LRBA deficiency display early-onset hypogam-
Coreceptor Complex maglobulinemia with autoimmunity and inflammatory bowel
CD21 (complement component C3d/Epstein-Barr virus receptor disease. They show reduced levels of at least two Ig isotypes
2) binds to membrane- IgM-bound antigen when complement (IgM, IgG, or IgA) and suffer from recurrent infections, autoim-
C3d is also attached to that antigen (Chapter 21). In association munity, and chronic pulmonary and GI disorders.
with CD81 and CD19, this coreceptor complex enhances the Patients with haploinsufficiency of CTLA-4 presented with
antigen-binding signal, promoting B-cell activation. Patients with autoimmunity, recurrent infections, benign lymphoproliferation,
mutations in CD19, CD21, and CD81 have been reported. 30 and varying levels of Igs and B-cells, and T-cell defects. 30,33
The BAFF–BAFFR (CVID4)–TACI (CVID2) Axis PKCδ Deficiency
The TNF family members B-cell activating factor of the TNF PKCδ plays a key role in BCR-mediated signaling downstream
family (BAFF) and a proliferation-inducing ligand (APRIL) of BTK and is important in B-cell proliferation, apoptosis, and
bind to two receptors, B-cell maturation antigen (BCMA) and tolerance. PKCδ deficiency presents with a variable phenotype,
transmembrane activator and calcium-modulator and cyclophilin with one affected patient having a CVID-like characteristics
ligand interactor (TACI), both members of the TNF-R family. (hypogammaglobulinemia and severe infections) and others
BCMA is expressed exclusively on B cells, whereas TACI is having lupus or autoimmune lymphoproliferative syndrome
expressed on activated T cells as well. A third receptor, BAFF-R, (ALPS)–like disease. 30