An Inherited Disorder of Lymphocyte Apoptosis: The Autoimmune Lymphoproliferative Syndrome

View larger version (153K): [in a new window]   Figure 1. Clinical, radiologic, and histologic features of patients with the autoimmune lymphoproliferative syndrome. A. Frontal view of National Institutes of Health patient 2. (Reproduced with permission from Sneller and colleagues [6].) B. Lymph node from patient 2 showing follicular hyperplasia and plasmacytosis (hematoxylin and eosin). (Courtesy of Dr. Elaine Jaffe.) C. Immunohistochemical stain of patient 2's lymph node for cells showing lymphocyte surface marker CD3. (Courtesy of Dr. Elaine Jaffe.) D. Immunohistochemical stain of patient 2's lymph node for cells showing lymphocyte surface marker CD4. (Courtesy of Dr. Elaine Jaffe.) E. 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.) F. 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.) G. 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 x200. For panels C to E, the stain used was immunoperoxidase.

View larger version (33K): [in a new window]   Figure 2. Mediators of lymphocyte apoptosis. Spanning the cell membrane are Fas (CD95) and tumor necrosis factor 1 (TNFR1) 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-B = nuclear factor-B; RIP = receptor interacting protein; TRADD = TNF receptor-associated death domain protein; TRAF 2 = TNF receptor-associated factor 2.

View larger version (12K): [in a new window]   Figure 3. Apoptosis after Fas (CD95) stimulation is impaired in patients with the autoimmune lymphoproliferative syndrome (ALPS). 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 (Norm) and seven unrelated patients with ALPS (Pt).

View larger version (21K): [in a new window]   Figure 4. The organization of theAPT1gene encoding Fas (CD95) (shown as numbered boxes separated by slashed lines indicating the intron sequences). The gray boxes covering exons 2 through 5 correspond to the extracellular cysteine-rich receptor domains (CRDs). 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 (It) and France (Fr). 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 (bp) homozygous deletion in exon 9 (Fr) found in a severely affected daughter of related parents (2). The region of the APT1 gene most often mutated is the intracellular death domain.

View larger version (19K): [in a new window]   Figure 5. A kindred of 11 persons in four generations with a mutation in the death domain of Fas. 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 (8).

View larger version (19K): [in a new window]   Figure 6. Proposed mechanism of autoimmunity in the autoimmune lymphoproliferative syndrome. Top. In normal persons, B-cell (B) and T-cell (T) 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 (APC). 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. Bottom. Interleukin (IL)-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.