Stephen E. Straus, MD; Michael Sneller, MD; Michael J. Lenardo, MD; Jennifer M. Puck, MD; Warren Strober, MD
The autoimmune lymphoproliferative syndrome (ALPS) affords novel insights into the mechanisms that regulate lymphocyte homeostasis and underlie the development of autoimmunity. This syndrome arises early in childhood in persons who inherit mutations in genes that mediate apoptosis, or programmed cell death. The timely deletion of lymphocytes is a way to prevent their accumulation and the persistence of cells that can react against the body's own antigens. In ALPS, defective lymphocyte apoptosis permits chronic, nonmalignant adenopathy and splenomegaly; the survival of normally uncommon “double-negative” CD3+ CD4 −CD8 −T cells; and the development of autoimmune disease. Most cases of ALPS involve heterozygous mutations in the lymphocyte surface protein Fas that impair a major apoptotic pathway. Detailed immunologic investigations of the cellular and cytokine profiles in ALPS show a prominent skewing toward a T-helper 2 phenotype; this provides a rational explanation for the humoral autoimmunity typical of patients with ALPS. Prospective evaluations of 26 patients and their families show an ever-expanding spectrum of ALPS and its major complications: hypersplenism, autoimmune hemolytic anemia, thrombocytopenia, and neutropenia. Defective apoptosis may also contribute to a heightened risk for lymphoma.
Frontal view of National Institutes of Health patient 2. (Reproduced with permission from Sneller and colleagues .) Lymph node from patient 2 showing follicular hyperplasia and plasmacytosis (hematoxylin and eosin). (Courtesy of Dr. Elaine Jaffe.) Immunohistochemical stain of patient 2's lymph node for cells showing lymphocyte surface marker CD3. (Courtesy of Dr. Elaine Jaffe.) Immunohistochemical stain of patient 2's lymph node for cells showing lymphocyte surface marker CD4. (Courtesy of Dr. Elaine Jaffe.) Immunohistochemical stain of patient 2's lymph node for cells showing lymphocyte surface marker CD8. Few of the cells that stain reddish brown for CD3 are CD4 or CD8 . (Courtesy of Dr. Elaine Jaffe.) Computed tomographic scan through the upper thorax and axillae and abdomen of patient 23 showing marked paratracheal, anterior mediastinal, and axillary adenopathy. (Courtesy of Dr. Nilo Avila.) Computed tomographic scan through the upper thorax and axillae and abdomen of patient 23 showing hepatosplenomegaly. (Courtesy of Dr. Nilo Avila.) For panels B to E, original magnifications were ×200. For panels C to E, the stain used was immunoperoxidase.
Spanning the cell membrane are Fas (CD95) and tumor necrosis factor 1 ( ) molecules. Each functions in homotrimers to bind ligands (Fas ligand and TNF, respectively) and trigger apoptosis. Cytoplasmic adapter molecules (FADD/MORT-1) bind the similar death domains of each receptor and then form complexes with caspase 8, which is cleaved to activate other caspase enzymes that ultimately mediate degradation of cellular DNA, cell death, and disintegration. FADD = Fas-associated death domain protein; FLICE/MACH 1 = FADD-like interleukin-1-converting enzyme/mediator of receptor-induced toxicity 1; NF-κB = nuclear factor-κB; RIP = receptor interacting protein; TRADD = TNF receptor-associated death domain protein; TRAF 2 = TNF receptor-associated factor 2.
Cell loss is the fraction of cycling T cells lost after 24 hours of Fas cross-linking by an agonistic monoclonal antibody. Shown are the results obtained by using cycling T cells from normal controls ( ) and seven unrelated patients with ALPS ( ).
The gray boxes covering exons 2 through 5 correspond to the extracellular cysteine-rich receptor domains ( ). The dark area of exon 9 is the cytoplasmic death-signaling domain. The localization and type of mutations in patients with the autoimmune lymphoproliferative syndrome are depicted above the exon drawing. The top line of symbols identifies the location of all published mutations from other research centers, including those in Italy ( ) and France ( ). The lower line of symbols depicts the mutations identified in National Institutes of Health patients. All of the mutations to date are single-nucleotide changes except for the 290-base pair ( ) homozygous deletion in exon 9 (Fr) found in a severely affected daughter of related parents . The region of the gene most often mutated is the intracellular death domain.
A spectrum of clinical presentations is seen among the affected family members; some exhibit lymphoproliferation, increased double-negative T cells, and autoimmunity. One member developed lymphoma. The squares represent males; the circles represent females; the arrow identifies the proband; and the slash identifies a family member who died. Reproduced with permission from Infante and colleagues .
In normal persons, B-cell ( ) and T-cell ( ) precursors undergo development under conditions that lead to the elimination of self-reactive cells. In the context of antigen stimulation, the mature B and T cells that emerge intact from this process interact through CD40/CD40L, and the B cells differentiate into antibody-producing cells ( ). As a further safeguard against the development of self-reactive cells, the latter are susceptible to Fas-mediated apoptosis unless they are co-stimulated by specific antigen. Interleukin ( )-10 overproduction induces intracellular antiapoptotic proteins (Bcl-2 family proteins); this increases the risk that self-reactive cells will persist during B-cell and T-cell development. This problem is compounded by defective Fas-mediated apoptosis of mature cells. The result is the expansion of self-reactive cells that mediate autoimmunity.
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Straus SE, Sneller M, Lenardo MJ, Puck JM, Strober W. An Inherited Disorder of Lymphocyte Apoptosis: The Autoimmune Lymphoproliferative Syndrome. Ann Intern Med. ;130:591–601. doi: 10.7326/0003-4819-130-7-199904060-00020
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Published: Ann Intern Med. 1999;130(7):591-601.
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