Page 1249 - Williams Hematology ( PDFDrive )

1224 Part IX: Lymphocytes and Plasma Cells Chapter 80: Immunodeficiency Diseases 1225

using a luciferase reporter assay gain-of-function mutations showed an autoimmune hemolytic anemia, thrombocytopenia, and neutropenia.
increase, whereas those with heterozygous loss of function mutations The incidence of lymphoma is estimated to be 9 percent in the National
182
causing AD-HIES had decreased activity. Institutes of Health cohort of 79 probands and consist of both Hodg-
kin and non-Hodgkin lymphoma. Both lymph nodes and spleen show
+
Cytotoxic T-Lymphocyte Antigen-4 Haploinsufficiency pronounced hyperplasia and contain a CD3 lymphocyte population of
–
+
–
Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is an inhibitory recep- which a large proportion consists of TCRαβ CD4 CD8 cells. This phe-
tor expressed by T lymphocytes including Tregs, and by B cells. While nomenon is also observed in blood lymphocytes from ALPS patients in
CD28 transmits a stimulatory signal to lymphocytes, CTLA-4 provides which the proportion of double-negative T cells is typically between
182
an inhibitory signal. CTLA-4 can also affect signaling in B cells by 5 and 20 percent (range: 1.5 to 68 percent). Many of these cells express
173
competing with CD28 for CD80/86 binding. MHC class II and secrete high levels of IL-4, IL-5, and IL-10.
In a recent report, heterozygous mutations in the CTLA4 gene were The FAS-mediated apoptosis pathway is important for the down-
observed in members of four unrelated families suffering from multiple regulation of antigen-induced immune responses and the elimination
autoimmune diseases, recurrent infections, and lymphocytic infiltrates of autoreactive lymphocytes. ALPS patients have mutations in genes
174
in a number of target organs. Affected patients developed hypogam- required for “programmed cell death.” The most common defect involves
maglobulinemia, CD4 lymphopenia, progressive loss of circulating B heterozygous (dominant) mutations in the gene encoding the T-cell
cells and defective/dysregulated Treg cells. Reduced CTLA-4 expression surface molecule FAS, also known as CD95 or TNFRSF6 (ALPS-FAS,
in T cells, B cells, and Tregs, and increased T- and B-cell apoptosis are formerly ALPS type Ia); rare patients with compound heterozygous or
characteristic findings and may contribute to the clinical phenotype. homozygous FAS-mutations (ALPS-FAS or type 0) have been reported.
In some patients, somatic mutations of FAS have been identified in double-
ITCH E3 Ubiquitin Protein Ligase Deficiency negative T cells (ALPS-sFAS or type 1m). A few families have been iden-
The clinical features of ITCH E3 ubiquitin protein ligase (ITCH) defi- tified with mutations affecting the FAS ligand (CD95L; TNFSF6) which
ciency caused by mutations in E3 ubiquitin ligase (ITCH/AIP4) include is responsible for ALPS-FASL or ALPS type Ib. Approximately 3 percent
dysmorphic facial features, failure to thrive and developmental delay. In of ALPS patients have mutations in caspase 10 (ALPS-CASP10 or ALPS
addition, immune dysregulation that is characterized by chronic inter- type II). Ten to 20 percent of patients with the ALPS phenotype do not
stitial pneumonitis, thyroiditis, type I diabetes, enteropathy, and hepa- have mutations in FAS, FASL, or caspases and are classified as ALPS-U
182
titis were common. This is a rare syndrome observed in a single large or ALPS type III. Because three Fas molecules form a trimeric com-
175
Amish kindred with 10 affected family members. ITCH can affect T-cell plex to interact with a FasL trimer, most families with ALPS have AD
anergy in mice because of defective FOXP3 expression. 176 inheritance (dominant negative effect) with variable penetrance (muta-
tions in caspase 8 and 10 are autosomal recessive).
AUTOIMMUNE POLYENDOCRINOPATHY,
CANDIDIASIS, AND ECTODERMAL DYSTROPHY Treatment
Immunosuppressive therapy including steroids, mycophenolate mof-
SYNDROME etil (MMF), and rituximab, has been used with variable success to
182
APECED is a rare autosomal recessive disorder, also known as auto- treat autoimmune symptoms. A recent clinical trial with sirolimus
immune polyglandular syndrome (APS) type I. The incidence is high achieved complete or near complete resolution of autoimmune cytope-
in certain isolated populations, for example, Finns, Iranian Jews, and nia, colitis, lymphadenopathy, and splenomegaly and all patients had a
183
Sardinians. Most patients with APECED present with chronic mucocu- reduction in double-negative T cells. Splenectomy is recommended
taneous candidiasis and endocrinopathies predominantly involving the only in patients with excessively large spleens or splenic rupture and
parathyroid and adrenal glands, less frequently the thyroid and the pan- requires lifetime antibiotic prophylaxis. The long-term prognosis is
creas. The syndrome is often associated with ectodermal manifestations guarded, but patients can achieve a normal life span.
such as dystrophic dental enamel and fingernails. APECED results
177
from mutations in the AIRE gene. AIRE expression is limited to medul-
lary thymic epithelial cells which express MHC class II and the costim- OTHER WELL-DEFINED
ulatory molecule CD80. These cells are endowed with the remarkable
ability to “promiscuously” express a wide variety of tissue-restricted IMMUNODEFICIENCY SYNDROMES
antigens derived from nearly all organs in the body. Expression of
178
these organ specific proteins allows for the negative selection of auto- WISKOTT-ALDRICH SYNDROME
reactive T cells or the generation of immunoregulatory FOXP3 T cells Definition
+
in the thymus. A lack of AIRE function causes decreased expression The Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder
of tissue-restricted antigens in the thymus, resulting in the escape of characterized by thrombocytopenia (Chap. 117) and small platelets,
autoreactive T-cell clones into the periphery. Autoantibodies against eczema, recurrent infections, immunodeficiency, and a high incidence
179
type 1 interferons, and against IL-17A, IL-17F and/or IL-22, were of autoimmune diseases and malignancies. A classic WAS phenotype
180
181
184
detected at high titers in most patients. Treatment for APECED is is generally associated with null-mutations of the gene that encode the
largely supportive. WAS protein (WASp). WASp is the key regulator of actin polymer-
ization in hematopoietic cells and has well-defined domains that are
AUTOIMMUNE LYMPHOPROLIFERATIVE involved in cytoplasmic signaling, cell locomotion, and immunologic
SYNDROME synapse formation. A milder phenotype, X-linked thrombocytopenia
(XLT), is often associated with mutations that result in expression of
Definition, Clinical Features, and Pathogenesis mutated protein. XLT patients have either no or very mild eczema and
ALPS is caused by defective apoptosis of lymphocytes, resulting in few problems, if any, with infections, autoimmunity, and malignancy.
185
nonmalignant lymphadenopathy, hepatosplenomegaly, and autoim- Amino acid substitutions within the GTPase-binding domain of WASp
mune disorders, which most commonly include Coombs-positive interfere with the intramolecular autoinhibitory mechanism, resulting

Kaushansky_chapter 80_p1211-1238.indd 1224 9/18/15 10:01 AM