Page 498 - Clinical Immunology_ Principles and Practice ( PDFDrive )

478 PARt fouR Immunological Deficiencies

the CD40 gene present with a phenotype indistinguishable from nutrition because of the presence of diarrhea or perirectal
HIGM1. abscesses. Oral ulcers, gingivitis, and perirectal ulcers are associated
with neutropenia, which may occur chronically or intermittently
HIGM Syndrome Type 4: As yet Unknown Causes in up to two-thirds of the patients. One-fifth of the patients
Patients presenting with a HIGM-like phenotype, but lacking develop sclerosing cholangitis that can lead to hepatic failure.
demonstrable mutations in genes previously associated with Cryptosporidiosis is present in half of these patients.
HIGM, such as CD40, CD154, NEMO, AID, and UNG, have Approximately one-quarter of patients with NEMO have
been grouped by some immunologists into a category termed autoimmunity or autoinflammation. An intestinal inflammatory
HIGM4. B cells from patients with HIGM4 demonstrate defective disorder may be the presenting problem with chronic diarrhea
class switch recombination, but normal somatic hypermutation. and abdominal pain, with a few having steroid dependence.
A genetic cause has yet to be identified, and spontaneous recovery Although originally distinguished by the high level of serum
has been reported. 19 IgM, IgM levels are often normal in affected individuals. IgG is
low in all patients. IgA and IgE are usually low but can be normal
HIGM Syndrome Type 5: UNG Deficiency or even elevated in one-tenth of the population. B- and T-cell
Activation-induced cytidine deaminase (AID) acts by deaminating counts are within the normal range in more than 90% of the
cytidine nucleotides in DNA, leaving a uracil nucleotide in its patients and depressed in the rest.
place. Uracil-DNA glycosylase (UNG; 12q23-24.1) can remove Lymphoid hyperplasia is a common finding in CD40–CD154
the uracil, permitting normal or error-prone repair. Patients axis patients with active infections. Individual nodes may become
with function-loss mutations on both alleles of the UNG gene extremely large, and some patients develop splenomegaly. Hilar
(HIGM5) have presented with a history of bacterial infections, adenopathy causes a diagnostic dilemma, as the risk of lymphoma
hyperplasia, increased serum IgM levels, and low IgG and IgA. is increased in HIGM. Although the lymphoid tissue is usually
histologically abnormal, reactive processes are far more common
NEMO than malignancy. Plasma cells can be abundant or sparse. Primary
The nuclear factor κB (NF-κB) essential modulator (NEMO) follicles are poorly developed. The most characteristic abnormality
plays a key role in the NF-κB pathway and consequently in the is the absence of germinal centers.
CD40 signal transduction pathway. NEMO acts as a scaffold for
two kinases important for the activation of NF-κB. The IKBKG AID–UNG Axis (HIGM2 and HIGM5)
gene encodes for NEMO and is located on the X-chromosome Infected patients with AID–UNG deficiency may present with
(Xq28). Hypomorphic mutations in the gene causes a syndrome giant germinal centers filled with highly proliferating B cells,
with affected individuals having ectodermal dysplasia. This results presumably as a result of intense antigen stimulation. Approxi-
in conical teeth, an absence of eccrine sweat glands, and a paucity mately one-fourth of patients with HIGM2, but not HIGM5,
of hair follicles. Patients with NEMO are considered to have a present with evidence of autoimmunity. Manifestations include
defect in innate immunity and cell-mediated immunity as a hemolytic anemia, thrombocytopenia, and autoimmune hepatitis.
result of defective NF-κB activation, which is important in Autoantibodies in these patients are of the IgM isotype.
Toll-like receptor (TLR) signaling. Laboratory abnormalities
include impaired natural killer (NK) cell function, impaired Origin and Pathogenesis
pneumococcal responses, hypogammaglobulinemia, antigen- CD40–CD154 Axis (HIGM1, HIGM3, and NEMO)
specific T-cell proliferative abnormalities, and increased serum CD154, a member of the tumor necrosis factor (TNF) family,
IgA levels. Less than 20% of patients with NEMO have HIGM is a type II transmembrane protein that is predominantly
and, thus in the past, have been grouped with the HIGM group. 20 expressed on mature, activated CD4 T cells. Its expression peaks
at 6–8 hours after activation and then falls to resting levels by
Clinical Manifestations 24–48 hours. CD154 is also expressed on CD4 thymocytes,
CD40-CD154 Axis (HIGM1, HIGM3, NEMO) activated CD8 T cells, NK cells, monocytes, basophils, mast cells,
The majority of patients with HIGM have inherited disruptions activated eosinophils, and activated platelets. Newborn T cells
in the CD40-CD154 axis. Lymph nodes and spleen are deprived are deficient in CD154 expression, although they can be induced
of germinal centers. Recurrent upper and lower respiratory tract to express the antigen if strongly stimulated.
infections are the most common clinical complaint. Patients CD40 is a member of the TNF receptor superfamily. It is
may also exhibit recurrent neutropenia with oral ulcers, perirectal constitutively expressed on pro-B, pre-B, and mature B cells, as
abscesses, and opportunistic infections with P. jiroveci, Toxoplasma well as on interdigitating cells, follicular dendritic cells (DCs),
gondii, or Cryptosporidium cholangitis. Autoimmunity is observed thymic epithelial cells, monocytes, platelets, and some carcinomas.
in approximately 20% of patients. Engagement of B-cell CD40 with CD154 on an activated T
Without prophylaxis, one third of patients develop P. jiroveci cell that also expresses Fas ligand (FasL or CD95L) leads to the
pneumonia, which can be the presenting problem in affected upregulation of Fas (CD95) on the B cell. NEMO is a part of
infants. These patients are also at risk for serious infections with the signaling pathway. If the B cell has concomitantly bound its
cytomegalovirus (CMV), adenovirus, Cryptococcus neoformans, cognate antigen and engaged the BCR-signaling pathway, it
or mycobacteria. These features signal a compromise in cell- becomes resistant to Fas-mediated apoptosis and expresses CD80/
mediated immunity as well as the characteristic flaw in antibody CD86 on the cell surface. The activated B cell can then engage
production, putting them in the spectrum of a combined CD28 on the T-cell surface and trigger the T cell to secrete its
immunodeficiency. cytokines. If the B cell fails to engage its BCR, the Fas pathway
Chronic diarrhea occurs in more than half of the patients. predominates, and the B cell is eliminated. With proper activation
Organisms include Cryptosporidium, G. lamblia, Salmonella, and of the CD40–CD154 pathway, exposure to interleukin-2 (IL-2)
Entamoeba histolytica. One quarter may require total parenteral and IL-10 induces production of IgM, IgG1, and IgA; and exposure