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This is a rare and recently described syndrome characterized by recurrent bacterial infections with subsequent lymphadenopathy due to autoimmune neutropenia. Laboratory results revealed a large proportion of alphabetaTCR positive, CD4 negative, CD8 negative, peripheral T cells (double negative T cells). This is a fundamental defect of apoptosis, or programmed cell death, and is manifested by decreased apoptosis, but normal Fas-mediated apoptosis.


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SYNONYMS Canale-Smith syndrome
Lymphoproliferative syndrome with autoimmunity

Immunophenotypic profiles in families with autoimmune lymphoproliferative syndrome.

Bleesing JJ, Brown MR, Straus SE, Dale JK, Siegel RM, Johnson M, Lenardo MJ, Puck JM, Fleisher TA.

Immunology Service, Department of Laboratory Medicine, Clinical Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

Blood 2001 Oct 15;98(8):2466-73 Abstract quote

Autoimmune lymphoproliferative syndrome (ALPS) type Ia is caused by inherited defects in apoptosis and is characterized by nonmalignant lymphoaccumulation, autoimmunity, and increased alpha/beta(+) double-negative T cells (alpha/beta(+)-DNT cells).

This study reports immunophenotypic findings in 166 members of 31 families with ALPS type Ia, associated with genetic mutations in the TNFRSF6 gene encoding Fas. The ALPS type Ia probands (n = 31) and relatives having both a Fas mutation and clinically proven ALPS (n = 28) showed significant expansion of CD8(+) T cells, alpha/beta(+)-DNT cells, gamma/delta(+)-DNT cells, CD3(+)/ HLA-DR(+) T cells, CD8(+)/CD57(+) T cells, and CD5(+) B cells. Relatives with Fas mutations, but without all the required criteria for ALPS (n = 42), had expansions of CD8(+) T cells, alpha/beta(+)-DNT cells, and gamma/delta(+)-DNT cells. Interestingly, relatives without a Fas mutation and with no features of ALPS (n = 65) demonstrated a small but significant expansion of CD8(+) T cells, both DNT cell subsets, and CD5(+) B cells.

As compared to unrelated healthy controls, lymphocyte subset alterations were greatest in the probands, followed by the relatives with mutations and ALPS. Probands and relatives with mutations and ALPS also showed a lower number of CD4(+)/CD25(+) T cells that, in combination with an independent increase in HLA-DR(+) T cells, provided a profile predictive of the presence of clinical ALPS.

Because quantitative defects in apoptosis were similar in mutation-positive relatives regardless of the presence of clinical ALPS, factors, other than modifiers of the Fas apoptosis pathway, leading to these distinctive immunophenotypic profiles most likely contribute to disease penetrance in ALPS.

Autoimmune lymphoproliferative syndrome (ALPS) in a child from consanguineous parents: a dominant or recessive disease?

van der Burg M, de Groot R, Comans-Bitter WM, den Hollander JC, Hooijkaas H, Neijens HJ, Berger RM, Oranje AP, Langerak AW, van Dongen JJ.

Department of Immunology, Erasmus University Rotterdam, The Netherlands.

Pediatr Res 2000 Mar;47(3):336-43 Abstract quote

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by autoimmune features and lymphoproliferations and is generally caused by defective Fas-mediated apoptosis.

This report describes a child with clinical features of ALPS without detectable Fas expression on freshly isolated blood leukocytes. Detection of FAS transcripts via real-time quantitative PCR made a severe transcriptional defect unlikely. Sequencing of the FAS gene revealed a 20-nucleotide duplication in the last exon affecting the cytoplasmic signaling domain. The patient was homozygous for this mutation, whereas the consanguineous parents and the siblings were heterozygous.

The patient reported here is a human homologue of the Fas-null mouse, inasmuch as she carries an autosomal homozygous mutation in the FAS gene and she shows the severe and accelerated ALPS phenotype. The heterozygous family members did not have the ALPS phenotype, indicating that the disease-causing FAS mutation in this family is autosomal recessive.



The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis.

Straus SE, Jaffe ES, Puck JM, Dale JK, Elkon KB, Rosen-Wolff A, Peters AM, Sneller MC, Hallahan CW, Wang J, Fischer RE, Jackson CM, Lin AY, Baumler C, Siegert E, Marx A, Vaishnaw AK, Grodzicky T, Fleisher TA, Lenardo MJ.

Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

Blood 2001 Jul 1;98(1):194-200 Abstract quote

Lymphomas were studied in kindreds with autoimmune lymphoproliferative syndrome (ALPS; Canale-Smith syndrome), a disorder of lymphocyte homeostasis usually associated with germline Fas mutations. Fas (CD95/APO-1) is a cell surface receptor that initiates programmed cell death, or apoptosis, of activated lymphocytes.

Lymphoma phenotype was determined by immunohistochemistry, frequency of CD3(+)CD4(-)CD8(-) T-cell-receptor alpha/beta cells by flow cytometry, nucleotide sequences of the gene encoding Fas (APT1, TNFRSF6), and the percentage of lymphocytes undergoing apoptosis in vitro. Of 223 members of 39 families, 130 individuals possessed heterozygous germline Fas mutations. Eleven B-cell and T-cell lymphomas of diverse types developed in 10 individuals with mutations in 8 families, up to 48 years after lymphoproliferation was first documented.

Their risk of non-Hodgkin and Hodgkin lymphomas, respectively, was 14 and 51 times greater than expected (each P <.001). Investigation of these 10 patients and their relatives with Fas mutations revealed that all had defective lymphocyte apoptosis and most had other features of ALPS. The tumor cells retained the heterozygous Fas mutations found in the peripheral blood and manifested defective Fas-mediated killing.

These data implicate a role for Fas-mediated apoptosis in preventing B-cell and T-cell lymphomas. Inherited defects in receptor-mediated lymphocyte apoptosis represent a newly appreciated risk factor for lymphomas.


Autoimmune lymphoproliferative syndrome associated with severe humoral immunodeficiency and monoclonal gammopathy.

Nanan R, Strobel P, Haas JP, Marx A, Kreth HW.

Universitats-Kinderklinik, Josef-Schneider-Str. 2, 97080 Wurzburg, Germany.

Ann Hematol 2002 Jun;81(6):332-5 Abstract quote

A boy of Caucasian origin with a new subtype of autoimmune lymphoproliferative syndrome (ALPS) is described.

The clinical picture was dominated by chronic noninfectious lymphadenopathy, splenomegaly, and recurrent bacterial infections. At the age of 6 the patient died of pneumococcal meningitis. Laboratory investigation disclosed impaired apoptosis in both B- and T-lymphocyte subsets and expanded populations of CD3+CD4-CD8- T lymphocytes.

Furthermore, marked dysregulation of humoral immune responses with transient expansion of monoclonal B cells, corresponding monoclonal gammopathy, and the presence of autoantibodies was found. Functional and molecular analysis revealed that Fas protein expression was normal, a mutation in the Fas gene was not found. Moreover, transcription of the downstream effector caspase-10 was unremarkable. This patient is unique compared to previously described patients as severe humoral immunodeficiency and monoclonal gammopathy are usually not described in patients with ALPS.

This case points out the important role of apoptosis in regulating the degree of humoral immune responses at a clonal level in humans and gives further evidence for the phenotypic diversity of ALPS.

Histologic Features of Sinus Histiocytosis With Massive Lymphadenopathy in Patients With Autoimmune Lymphoproliferative Syndrome.

Maric I, Pittaluga S, Dale JK, Niemela JE, Delsol G, Diment J, Rosai J, Raffeld M, Puck JM, Straus SE, Jaffe ES.

From the *Hematopathology Section, Center for Cancer Research, National Cancer Institute, Bethesda, MD; daggerLaboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD; double daggerClinical Pathology Department, Clinical Center, National Institutes of Health, Bethesda, MD; section signINSERM U563, Departement d'Oncogenese et Signalisation dans les Cellules Hematopoietiques, Hopital Purpan, Toulouse Cedex, France; parallelDepartment of Pathology, National Cancer Institute Milan, Italy; and paragraph signGenetics and Molecular Biology Branch, National Human Genome Research Institute, Bethesda, MD. Dr. Diment's current affiliation is Department of Pathology, Kaplan Medical Center, Rehovot, Israel.
Am J Surg Pathol. 2005 Jul;29(7):903-911. Abstract quote

Autoimmune lymphoproliferative syndrome (ALPS) is an inherited disorder associated with defects in Fas-mediated apoptosis, characterized most often by childhood onset of lymphadenopathy, splenomegaly, hypergammaglobulinemia, and autoimmune phenomena. Children with sinus histiocytosis with massive lymphadenopathy (SHML) have a somewhat similar clinical phenotype in which prominent adenopathy also is associated with hypergammaglobulinemia, and autoimmune phenomena are reported in 10-15% of cases.

We observed histopathological features of SHML in the lymph nodes of some of our ALPS patients, further suggesting an association between these two disorders. We, thus, reviewed the lymph nodes from 44 patients ALPS type Ia, all of whom were confirmed to have germline mutations in the TNFRSF6 gene encoding Fas (CD95/Apo-1). Eighteen of 44 (41%) patients had a histiocytic proliferation resembling SHML. The affected patients included 15 males and 3 females ranging in age from 11 months to 30 years at the time of the LN biopsy. The lymph nodes contained S-100+ histiocytes with characteristic nuclear features of SHML, and showed evidence of emperipolesis in both hematoxylin and eosin (H and E) and immunostained sections. The extent of the histiocytic proliferation was variable, being confluent in 2 cases, multifocal in 13, and only evident as isolated SHML-type histiocytes in 3. In lymph nodes without confluent SHML changes, increased numbers of CD3CD4CD8 (double negative) alphabeta T-cells, also negative for CD45RO, a feature of ALPS, could be identified in the paracortex. Furthermore, because SHML shares many clinical features with ALPS, we sought evidence of ALPS in sporadic SHML. We attempted to sequence TNFRSF6 DNA from archived tissue of 14 cases of Rosai-Dorfman disease. Full sequencing of the gene was successful in 4 of the cases; no mutations were identified. Nevertheless, our observations suggest that histologic features of SHML are part of the pathologic spectrum of ALPS type Ia.

It remains to be determined if some cases of apparently sporadic SHML may be associated with heritable defects in Fas-mediated apoptosis.



A new disorder of lymphocyte apoptosis: combination of autoimmunity, infectious lymphadenopathy, double negative T cells, and impaired activation-induced cell death.

Hundt M, Posovszky C, Schmidt RE.

Department of Clinical Immunology, Hannover Medical School, Germany.

Immunobiology 2002 Dec;206(5):514-8 Abstract quote

A new symptom-complex is described characterized by manifestations of autoimmune disease, infectious lymphadenopathy, double negative T cells, and impaired activation-induced cell death that developed in late adolescence. Similarities, but also significant differences, to autoimmune lymphoproliferative syndromes (ALPS, Canale-Smith syndrome) and autoimmune lymphoproliferative disease (ALD, Dianzani syndrome), were observed.

The main clinical features were recurrent bacterial infections with subsequent lymphadenopathy due to autoimmune neutropenia. Laboratory results revealed a large proportion of alphabetaTCR positive, CD4 negative, CD8 negative, peripheral T cells, and a decreased apoptosis upon activation with phytohemagglutinin and interleukin 2, but normal Fas-mediated apoptosis. Genetic investigations excluded mutations in Fas gene death domain and in the 4 exons of Fas ligand gene.

Despite unknown pathogenesis, this new syndrome might belong to the growing group of diseases with defects in apoptosis.

Autoimmune lymphoproliferative syndrome, a disorder of apoptosis.

Jackson CE, Puck JM.

Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-4442, USA.

Curr Opin Pediatr 1999 Dec;11(6):521-7 Abstract quote

Autoimmune Lymphoproliferative Syndrome (ALPS) is a recently recognized disease in which a genetic defect in programmed cell death, or apoptosis, leads to breakdown of lymphocyte homeostasis and normal immunologic tolerance. Some authors have referred to ALPS as Canale-Smith syndrome or lymphoproliferative syndrome with autoimmunity.

Patients with ALPS have chronic enlargement of the spleen and lymph nodes, various manifestations of autoimmunity, and elevation of a normally rare population of "double negative T cells" (DNTs), T lymphocytes bearing alpha beta T cell receptors and expressing neither cluster differentiation (CD)4 nor CD8 surface antigens. When lymphocytes from patients with ALPS are cultured in vitro, they are resistant to apoptosis as compared to cells from healthy controls.

Most patients with ALPS have mutations in a gene now named TNFRSF6 (tumor necrosis factor receptor gene superfamily member 6). This gene, previously known as apoptosis antigen 1 (APT1), encodes the cell surface receptor for the major apoptosis pathway in mature lymphocytes; this receptor has also had many names, including Fas (to be used here), CD95, and APO-1.

ALPS is subdivided into: 1) Type Ia, ALPS with mutant Fas; 2) Type Ib, lymphadenopathy and mutation in the ligand for Fas in one patient with systemic lupus erythematosus; 3) Type II, ALPS with mutant caspase 10; and 4) Type III, ALPS as yet without any defined genetic cause.

Identification of new Fas mutations in a patient with autoimmune lymphoproliferative syndrome (ALPS) and eosinophilia.

Aspinall AI, Pinto A, Auer IA, Bridges P, Luider J, Dimnik L, Patel KD, Jorgenson K, Woodman RC.

Immunology Research Group, University of Calgary, Canada.


Blood Cells Mol Dis 1999 Jun-Aug;25(3-4):227-38 Abstract quote

Autoimmune lymphoproliferative syndrome (ALPS) is a rare, newly recognized, chronic lymphoproliferative disorder in children and is characterized by lymphadenopathy, splenomegaly, pancytopenia, autoimmune phenomena and expansion of double-negative (DN) T lymphocytes (TCR alpha beta+, CD4-, CD8-).

Defective lymphocyte apoptosis caused by mutations of the Fas (CD95) gene has been linked in the pathogenesis of ALPS, as binding of Fas-ligand to Fas can trigger apoptosis. Of the ALPS cases reported to date, point mutations, frameshifts and silent mutations in Fas all have been identified.

We report two new point mutations in Fas in a child with ALPS and eosinophilia; studies on other family members established the pattern of inheritance for these mutations. Flow cytometric analysis of blood and tissues (spleen, lymph node, bone marrow) revealed abnormally expanded populations of DN T lymphocytes. Furthermore, activated lymphocytes and IFN gamma-activated eosinophils were resistant to Fas-mediated apoptosis. Eosinophil resistance to Fas-mediated apoptosis has not been previously described in ALPS. Sequencing of Fas revealed two separate mutations not previously reported. One mutation, a C to T change at base 836, was a silent mutation inherited from the mother, while the second mutation, a C to A change at base 916, caused a non-conservative amino acid substitution in the death domain of Fas, changing a threonine to a lysine. This mutation is associated with a predicted change in the structure of a part of the death domain from a beta-pleated sheet to an alpha-helix.

We speculate that the mutation in the death domain prevents the interaction of Fas with intracellular mediators of apoptosis and is responsible for the autoimmune manifestations of ALPS and the abnormal lymphocytosis and eosinophilia in this patient.




Aberrant T-cell antigen receptor-mediated responses in autoimmune lymphoproliferative syndrome.

Goldman FD, Vibhakar R, Puck JM, Straus SE, Ballas ZK, Hollenback C, Loew T, Thompson A, Song K, Cook RT.

Department of Pediatrics, University of Iowa Hospitals and Clinics and Veterans Affairs Medical Center, Iowa City, 52242, USA.

Clin Immunol 2002 Jul;104(1):31-9 Abstract quote

Autoimmune Lymphoproliferative Syndrome (ALPS) is a disorder of defective lymphocyte apoptosis due to mutations of the Fas receptor and other molecules in the Fas signaling pathway. In addition to accumulation of CD4(-) CD8(-) double-negative (DN) T cells, many patients display a dysregulated cytokine pattern with dysfunctional T cells, suggesting Fas defects may impact pathways of T-cell activation/differentiation.

Here, we report two novel mutations in the Fas receptor resulting in an ALPS phenotype. Utilizing flow cytometry, we found anti-CD3 activated CD4(+) T cells from these patients were incapable of fully upregulating activation markers (CD25, CD69, and CD40L) or producing interferon-gamma and IL-2. Additionally, DN T cells were unable to transduce proximal T-cell antigen receptor signals or produce cytokines. Furthermore, DN T cells overexpressed CD57 and phenotypically resembled end-stage effector cells.

As DN T cells were essentially anergic, the clinical manifestations of autoimmunity are more likely to be a consequence of aberrant cytokine secretion within the CD4(+) T-cell subpopulation.


FAS Gene Mutation in a Case of Autoimmune Lymphoproliferative Syndrome Type IA With Accumulation of gammadelta+ T Cells.

Van Den Berg A, Tamminga R, De Jong D, Maggio E, Kamps W, Poppema S.

Am J Surg Pathol 2003 Apr;27(4):546-53 Abstract quote

A 6-month-old girl presented to the hospital with cervical lymphadenopathy and hepatosplenomegaly. She was known to have an enlarged spleen, anemia, and thrombocytopenia since the age of 1 month. A lymph node biopsy showed a diffuse proliferation of blasts with few remnants of follicles.

The blasts were CD3+CD57+CD4-CD8-, consistent with the usual autoimmune lymphoproliferative syndrome phenotype. However, these double negative T cells stained positive for gammadelta T-cell receptors, whereas double negative T cells in patients with autoimmune lymphoproliferative syndrome usually bear alphabeta T-cell receptor.

Mutation analysis of the FAS gene revealed a mutation in the death domain of the FAS gene, which is a frequent finding in patients with autoimmune lymphoproliferative syndrome. Based on these results, the diagnosis of autoimmune lymphoproliferative syndrome was established. RT-PCR analysis of the affected lymph node tissue revealed a strong upregulation of interleukin 10 and a moderate upregulation of interferon-gamma expression compared with normal tissue.

Our findings indicate that autoimmune lymphoproliferative syndrome can result in a prominent proliferation of gammadelta+ double negative T cells. It is important to distinguish this benign polyclonal proliferation from neoplastic gammadelta+ T-cell proliferations, such as hepatosplenic gammadelta T-cell lymphomas. Factors contributing to the accumulation of these gammadelta+ double negative T cells may be an unidentified infection in combination with the young age of onset in this patient.

Missense mutations in the Fas gene resulting in autoimmune lymphoproliferative syndrome: a molecular and immunological analysis.

Bettinardi A, Brugnoni D, Quiros-Roldan E, Malagoli A, La Grutta S, Correra A, Notarangelo LD.

Consorzio per le Biotecnologie, Servizio di Immunologia Clinica, Spedali Civili di Brescia, Italy.


Blood 1997 Feb 1;89(3):902-9 Abstract quote

Programmed cell death (or apoptosis) is a physiological process essential to the normal development and homeostatic maintenance of the immune system. The Fas/Apo-1 receptor plays a crucial role in the regulation of apoptosis, as demonstrated by lymphoproliferation in MRL-lpr/lpr mice and by the recently described autoimmune lymphoproliferative syndrome (ALPS) in humans, both of which are due to mutations in the Fas gene.

We describe a novel family with ALPS in which three affected siblings carry two distinct missense mutations on both the Fas gene alleles and show lack of Fas-induced apoptosis. The children share common clinical features including splenomegaly and lymphadenopathy, but only one developed severe autoimmune manifestations.

In all three siblings, we demonstrated the presence of anergic CD3+CD4-CD8- (double negative, [DN]) T cells; moreover, a chronic lymphocyte activation was found, as demonstrated by the presence of high levels of HLA-DR expression on peripheral CD3+ cells and by the presence of high levels of serum activation markers such as soluble interleukin-2 receptor (slL-2R) and soluble CD30 (sCD30).



Autoimmune lymphoproliferative syndrome: report of two cases and review of the literature.

Oren H, Ozkal S, Gulen H, Duman M, Ucar C, Atabay B, Yilmaz S, Kargi A, Irken G.

Department of Pediatric Hematology, Dokuz Eylul University Faculty of Medicine, 35340 Balcova, Izmir, Turkey.

Ann Hematol 2002 Nov;81(11):651-3 Abstract quote

Autoimmune lymphoproliferative syndrome (ALPS) is a rare disease occurring in childhood. Recently, it has been shown that heritable mutations in Fas or Fas ligand genes, which regulate lymphocyte survival by triggering apoptosis of lymphocytes, are the most frequent cause of ALPS. Patients with ALPS frequently have lymphadenopathy, splenomegaly and hepatomegaly, especially at young ages.

A positive result of the Direct Coomb's test, autoimmune hemolytic anemia, and idiopathic thrombocytopenic purpura are the most common features of autoimmunity in patients with ALPS. Elevated numbers and percentages (>1%) of double-negative (CD4-CD8-) T cells, and characteristic pathologic findings in lymph nodes or spleen are other important diagnostic features. In this report, we present the clinical, immunologic, and pathologic features of two children who were diagnosed with ALPS. The early recognition of ALPS in children with enlarged lymph nodes, hepatosplenomegaly, and autoimmune hematologic features has important diagnostic and prognostic value in avoiding expensive and time-consuming studies and unnecessary treatments.

The ratio of CD4-CD8- T cells, immunoglobulin levels and the histopathologic features of lymph nodes should be rapidly determined in these patients in order to establish an early diagnosis and treatment.

The clinical spectrum in a large kindred with autoimmune lymphoproliferative syndrome caused by a Fas mutation that impairs lymphocyte apoptosis.

Infante AJ, Britton HA, DeNapoli T, Middelton LA, Lenardo MJ, Jackson CE, Wang J, Fleisher T, Straus SE, Puck JM.

Department of Pediatrics, University of Texas Health Science Center at San Antonio 78284-7810, USA.


J Pediatr 1998 Nov;133(5):629-33 Abstract quote

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by chronic, histologically benign splenomegaly and generalized lymphadenopathy, hypergammaglobulinemia, and autoantibody formation. ALPS has been attributed to defective programmed cell death of lymphocytes, most often arising as a result of mutations in the gene encoding the lymphocyte apoptosis receptor Fas/APO-l/CD95.

We identified a novel mutation in the intracellular apoptosis signaling domain of Fas in 11 members of a family, individual members of which have been monitored for up to 25 years, with 1 or more features of ALPS.

This study of a large number of family members carrying the same Fas defect demonstrates that ALPS is inherited in an autosomal dominant fashion but with a high degree of variability in clinical expression. Although 1 affected individual died of postsplenectomy sepsis and 1 has been treated for lymphoma, the Fas mutation in this family has been compatible with a healthy adulthood, as clinical features of ALPS have receded with increasing age.



Light microscopic, immunophenotypic, and molecular genetic study of autoimmune lymphoproliferative syndrome caused by fas mutation.

Kraus MD, Shenoy S, Chatila T, Hess JL.

Lauren V. Ackerman Laboratory of Surgical Pathology, Washington University Medical Center, 660 South Euclid Avenue, St. Louis, MO 63110, USA.

Pediatr Dev Pathol 2000 Jan-Feb;3(1):101-9 Abstract quote

This case provides a complete light microscopic, immunophenotypic, and molecular genetic analysis of autoimmune lymphoproliferative syndrome (ALPS), a rare benign cause of dramatic lymphadenopathy with atypical histology and phenotype that may be mistaken for malignancy.

The patient is 3-year-old child who was first clinically evaluated at the age of 16 months because of marked generalized lymphadenopathy and hepatosplenomegaly. Histologic sections of a cervical lymph node demonstrated a marked paracortical proliferation of occasional small and intermediate-sized lymphocytes and numerous large immunoblasts, the majority of which displayed a CD3(+), CD43(+), CD45RO(-) (OPD4, UCHL1) CD4(-), CD8(-) phenotype on paraffin sections, and which had a CD2(+), CD3(+), CD5(+), CD56(-), Tdelta1(-), [CD4(-), CD8(-)] double negative profile on flow cytometric analysis.

Southern blot analysis did not identify a clonal T or B cell population, and sequencing of the fas gene identified a mutation that caused a single amino acid substitution in the intracytoplasmic death domain of this protein. An enriched population of CD45RO-negative naive T cells in the paracortex may explain the atypical histologic and immunophenotypic features of this case.

Greater awareness of this heritable lymphoproliferative disorder will facilitate its recognition and minimize the possibility of misdiagnosis.

Pathological findings in human autoimmune lymphoproliferative syndrome.

Lim MS, Straus SE, Dale JK, Fleisher TA, Stetler-Stevenson M, Strober W, Sneller MC, Puck JM, Lenardo MJ, Elenitoba-Johnson KS, Lin AY, Raffeld M, Jaffe ES.

Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

Am J Pathol 1998 Nov;153(5):1541-50 Abstract quote

The defects in lymphocyte apoptosis that underlie the autoimmune lymphoproliferative syndrome (ALPS) are usually attributable to inherited mutations of the CD95 (Fas) gene.

In this report, we present the histopathological and immunophenotypic features seen in the lymph nodes (n = 16), peripheral blood (n = 10), bone marrow (n = 2), spleen (n = 3), and liver (n = 2) from 10 patients with ALPS. Lymph nodes showed marked paracortical hyperplasia. Interfollicular areas were expanded and populated by T cell receptor-alphabeta CD3+ CD4-CD8- (double-negative, DN) T cells that were negative for CD45RO. CD45RA+ T cells were increased in all cases studied. The paracortical infiltrate was a result of both reduced apoptosis and increased proliferation, as measured by in situ detection of DNA fragmentation and staining with MIB-1, respectively.

The paracortical proliferation may be extensive enough to suggest a diagnosis of malignant lymphoma. Many of the paracortical lymphocytes expressed markers associated with cytotoxicity, such as perforin, TIA-1, and CD57. CD25 was negative. In addition, most lymph nodes exhibited florid follicular hyperplasia, often with focal progressive transformation of germinal centers; in some cases, follicular involution was seen.

A polyclonal plasmacytosis also was present. The spleens were markedly enlarged, more than 10 times normal size. There was expansion of both white pulp and red pulp, with increased DN T cells. DN T cells also were observed in liver biopsies exhibiting portal triaditis. In the peripheral blood, the T cells showed increased expression of HLA-DR and CD57 but not CD25. CD45RA+ T cells were increased in the four cases studied. Polyclonal B cell lymphocytosis with expansion of CD5+ B cells was a characteristic finding. Taken together, the histopathological and immunophenotypic findings, particularly in lymph nodes and peripheral blood, are sufficiently distinctive to suggest a diagnosis of ALPS.

Of note, two affected family members of one proband developed lymphoma (T-cell-rich B-cell lymphoma and nodular lymphocyte predominance Hodgkin's disease, respectively).



Dominant expression of interleukin 10 but not interferon gamma in CD4(-)CD8(-)alphabetaT cells of autoimmune lymphoproliferative syndrome.

Ohga S, Nomura A, Takahata Y, Ihara K, Takada H, Wakiguchi H, Kudo Y, Hara T.

Department of Paediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Br J Haematol 2002 Nov;119(2):535-8 Abstract quote

Cytokine expression in CD4-CD8- double-negative (DN) T cells of autoimmune lymphoproliferative syndrome (ALPS) was analysed. Two patients with DN alphabetaT-cell expansion showed higher serum interleukin 10 (IL-10) levels than one patient without it. Intracellular flow-cytometric analysis indicated the IL-10-expressing CD3+CD4-CD8- cells in patients with lymphoproliferation.

Quantitative real-time polymerase chain reaction revealed approximately 100 times higher IL-10, but not interferon-gamma or transforming growth factor-beta in DN than in single-positive T cells. IL-10 was exclusively expressed in DN alphabeta but not (gamma)(delta)T cells.

Circulating DN alphabetaT cells may constitutively express IL-10 and contribute to the ALPS phenotype.



Correction of autoimmune lymphoproliferative syndrome by bone marrow transplantation.

Sleight BJ, Prasad VS, DeLaat C, Steele P, Ballard E, Arceci RJ, Sidman CL.

Department of Pediatrics, Children's Hospital Medical Center, Cincinnati, OH, USA.

Bone Marrow Transplant 1998 Aug;22(4):375-80 Abstract quote

This report describes a child with a severe phenotype of autoimmune lymphoproliferative syndrome (ALPS) who developed progressive disease requiring stem cell transplantation. This severe form of ALPS was associated with a novel Fas gene splice site mutation that resulted in functional deletion of exons 8 and 9.

While this child shared many clinical features with previously described ALPS cases, including massive lymphadenopathy and circulating alphabeta+ CD3+CD4-CD8-T cells, his disease progressed despite immunosuppressive therapy to a clinically aggressive oligoclonal lymphoproliferation which resembled a diffuse large cell non-Hodgkin's lymphoma. After partial remission was achieved with cytotoxic therapy the patient underwent BMT from an unrelated donor.

This is the first reported case of ALPS in which BMT was successfully attempted for correction of a Fas deficiency.

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