Wiskott-Aldrich syndrome is a rare X chromosome-linked primary immunodeficiency syndrome associated with an increased incidence of infections, autoimmune disorders and neoplasms. We present the case of a year-old man with a diagnosis of Wiskott-Aldrich syndrome with ileitis as a form of presentation of a lymphoproliferative syndrome. The ileitis, in the context of the patient, represents a clinical challenge given the large number of differential diagnoses inflammatory bowel disease, infections, neoplasms and lymphoproliferative diseases , so it usually requires anatomopathological diagnosis and particular considerations regarding the subsequent specific treatment. Keywords: Wiskott-Aldrich; ileitis; lymphoproliferative syndrome. This site needs JavaScript to work properly. Please enable it to take advantage of the complete set of features!

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Autoimmunity and Immunodeficiency View all 10 Articles. WASP is a cytoplasmic protein that regulates the formation of actin filaments in hematopoietic cells. Both cellular and humoral immune defects in WAS patients contribute to the onset of severe clinical manifestations, in particular microthrombocytopenia, eczema, recurrent infections, and a high susceptibility to develop autoimmunity and malignancies.

Many groups have widely explored immune cell functionality in WAS partially explaining how cellular defects may lead to pathology. However, the mechanisms underlying the occurrence of autoimmune manifestations have not been clearly described yet.

In the present review, we report the most recent progresses in the study of immune cell function in WAS that have started to unveil the mechanisms contributing to autoimmune complications in WAS patients.

Affected patients demonstrate both cellular and humoral immunodeficiency, high susceptibility to infections, eczema, microthrombocytopenia, and increased risk of autoimmune disorders and lymphomas Bosticardo et al. Figure 1. Wiskott—Aldrich syndrome structure and interacting proteins.

The severity of disease, measured on the basis of the classification proposed by Zhu et al. Table 1. WAS scoring system according to Zhu et al. A score from one to two identifies patients affected from a milder form of the disease, named X-Linked Thrombocytopenia XLT; Villa et al. Localized eczema and occasional respiratory infections, in addition to microthrombocytopenia, identify score 2 of the disease. Patients who develop microthrombocytopenia, associated with persistent but therapy-responsive eczema or infections receive a score of 3, whereas a score of 4 is given if eczema or infections do not respond to treatments.

Finally, score 5 is assigned to patients developing autoimmunity or tumors. Wiskott—Aldrich Syndrome gene mutations are scattered throughout the entire length of the WAS gene, although some hot spots have been identified Ochs and Thrasher, Mutations that abolish WASP expression are mainly associated with a severe clinical phenotype full blown WAS and a life expectancy below 20 years of age Jin et al.

On the contrary, missense mutations, which result in residual expression of a full-length point-mutated WASP, are often associated with XLT Villa et al.

All patients harboring mutations in the WAS gene are micro-thrombocytopenic, although intermittent X-Linked Thrombocytopenia iXLT is observed in some patients with substantial protein expression Notarangelo et al. The revertant mutation can occur at various stages of hematopoietic differentiation thus conferring high selective advantage to revertant cells over mutated cell populations not expressing WASP.

Although many reports describe the occurrence of this phenomenon, it is still not clear whether the presence of somatic mosaicism might correlate with a better clinical course of the disease Davis and Candotti, ; Trifari et al. Figure 2. Schematic view of cellular defects described in WASP-deficient cells.

Motility, adhesion and migration of B cells are also defective Westerberg et al. Figure 3. The red boxes indicate the main pathways induced downstream of these receptors. The role of WASP in these pathways is indicated by stars close to interacting molecules: red stars show the interactions that are demonstrated, whereas the blue stars with question marks show hypothetical involvement of WASP in TLR signaling pathways. The mechanism underlying thrombocytopenia is not completely understood.

One possible explanation could be an abnormal platelet clearance induced by an increased exposure of phosphatidylserine on the outer plasma membrane of WASP-deficient platelets Shcherbina et al.

Another mechanism of platelet reduction that needs to be investigated more in detail, is the elimination mediated by autoimmune reaction. The second most common manifestation in WAS patients is the eczema. Indeed, it has been shown that WAS patients with residual WASP expression develop moderate or transient form of the disease, whereas most of WASP-negative patients develop severe, treatment-resistant eczema Imai et al. Although higher IgE levels may represent a possible cause of eczema, the correlation between increased IgE levels and eczema has not yet been demonstrated.

WAS patients are highly susceptible to infections by bacteria, viruses, and fungi Imai et al. Of note, WASP-negative patients are more frequently affected by bacterial infections otitis media, skin abscess, pneumonia, enterocolitis, meningitis, sepsis, urinary tract infection, and others , viral infections Herpes simplex and Cytomegalovirus and fungal infections Candida spp.

Malignancies can affect adolescent and young adult WAS patients more than infants Sullivan et al. Epstein—Barr virus EBV -positive B cell lymphoma is most frequently reported, but also myelodysplasia can be observed in some patients Imai et al. WAS patients with autoimmune diseases constitute a high-risk group with poor prognosis.

Moreover, autoimmunity is associated with a higher risk of a later development of tumors and an increased risk of mortality Sullivan et al.

A better understanding of the mechanisms underlying autoimmunity in WAS would be crucial for the development of more effective therapies for the management of these manifestations in WAS and could also provide new insights in the pathogenesis of autoimmunity in PIDs. Moreover, multiple autoimmune manifestations can be observed.

In most cases, and in all cases of hemolytic anemia, the onset of autoimmune complications occurs early in life 0—5 years; Dupuis-Girod et al. Although these studies have been performed on WAS mouse model, they clearly suggest a possible mechanism for the pathogenesis of glomerulonephritis in WAS patients. Clinical management of WAS patients is a significant challenge since, with the exception of Bone Marrow Transplantation BMT , most available therapies are not curative. Intravenous immunoglobulins IVIG and antibiotic prophylaxis are often used to reduce the risk of infections in WAS patients, but it is not clear whether these treatments effectively reduce the incidence of life-threatening infections Conley et al.

Splenectomy significantly increases and often normalizes the platelet counts Corash et al. However, it does not fully overcome the risk of bleeding and further predisposes to sepsis, obliging the patients to life-long antibiotic prophylaxis Mullen et al. Relapse of thrombocytopenia has been described in a fraction of splenectomized WAS patients Corash et al. Of note, in some cases, thrombocytopenia was found to be autoantibody-mediated and also associated with hemolytic anemia or cerebral vasculitis Dupuis-Girod et al.

Therefore, splenectomy is indicated only in severe cases, for which there is no prospect for other curative interventions. Treatment with human recombinant Interleukin 2 hrIL-2 appeared to be effective in reducing herpes virus infections and improving dermatitis in a WAS patient Azuma et al.

Administration of hrIL-2 ameliorated proliferation of cultured T cells from one patient Azuma et al. The treatment of choice for autoimmune manifestations in WAS patients consists of steroids, alone, or in association with cyclosporine Dupuis-Girod et al.

Cyclophosphamide and azathioprine are also used in some cases and are effective in a small percentage of cases. Patients with severe autoimmune thrombocytopenia after splenectomy are usually treated with IVIG, high-dose steroids, azathioprine, and cyclophosphamide.

Other autoimmune or inflammatory complications are generally treated with steroids, in association with cyclosporine, and are effective in the majority of skin vasculitis, arthritis, bowel inflammatory disease and renal disease cases Dupuis-Girod et al.

Anti-CD20 monoclonal antibody therapy has been also performed for the treatment of autoimmune hemolytic anemia in some patients. This treatment results effective in correcting the anemia, but it may need repeated courses due to relapse of the disease Ship et al. Autoimmune manifestations appeared at a median of 1.

The median duration of autoimmunity was 4 years range: 1—20 years. Ozsahin and colleagues investigated whether patients developing autoimmunity after HSCT had autoimmune manifestations also before treatment. Overall, 17 patients had autoimmune manifestations before transplantation that persisted thereafter in seven of them.

A very interesting observation in both retrospective studies was the strong correlation between autoimmunity occurrence and the chimerism pattern. Overall, incomplete reconstitution of lymphocyte counts and incidence of autoimmunity were higher in patients with a lower degree of chimerism in both lymphoid and myeloid compartments as compared to patients with full chimerism Ozsahin et al.

T and B cells, NK cells, and monocytes were also functionally corrected resulting in improved clinical conditions. Signs and symptoms of autoimmunity disappeared in both patients within the first year after GT. In one of the two reported patients, severe autoimmune hemolytic anemia, autoimmune thrombocytopenia, and autoimmune neutropenia disappeared; whereas severe eczema resolved in the second patient.

Preclinical data in the murine model indicate that the LV-mediated GT approach is effective in restoring immune cell functionality Blundell et al. Nevertheless, data from the clinical study are needed to provide definitive evidence of the efficacy and safety of this novel therapeutic approach. T cells are significantly reduced in peripheral blood of WAS patients and show a defective proliferation in response to TCR stimulation by CD3-specific antibody, although this defect is present only at low doses of agonistic antibody Molina et al.

T cell activation is regulated by the formation of the IS, a polarized cluster of TCR, costimulatory molecules, signaling molecules, and integrins at the T cell:antigen presenting cell APC interface. To promote their lateral movement on the plasma membrane, the molecules being recruited to the IS are associated with specific cholesterol-enriched membrane microdomains, called lipid rafts.

It is commonly assumed that autoimmunity is a consequence of the breakdown of central or peripheral tolerance to self-antigens. Susceptibility of WAS patients to develop autoimmune diseases can be at least in part explained by nTreg cell dysfunction. Recent findings have demonstrated that also T effector cells are implicated in tolerance breakdown in WAS.

Indeed, in response to restimulation through the TCR, activated T cells can undergo apoptosis, and this event is called restimulation-induced cell death RICD; Lenardo, ; Siegel et al.

RICD process contributes to the maintenance of peripheral immune tolerance by eliminating T cells responding to prolonged presence of antigens, such as self-antigens and persistent pathogen antigens Critchfield et al.

Together with nTreg cell defects, these recent findings highlight the role played by effector T cells in the maintenance of T cell tolerance in WAS. These data revealed the complex role of B cells that work independently or synergistically with other components of the innate and adaptive immune system to drive autoimmune pathogenesis.

For many years, the functionality of B cells in WAS patients was poorly investigated. The presence of a skewed distribution of serum Ig isotypes reduced IgM, normal IgG, and elevated IgE and IgA levels and a reduced or absent antibody production to polysaccharides and other T cell-independent antigens Golding et al.

In the last decade, it has been clearly defined that the lack of WASP causes defects in the cytoskeletal functions of B cells, including adhesion, migration, and homing Westerberg et al. These defects may compromise the capacity of B cells to be properly activated and reach the site of infection contributing to the inability of the immunodeficient host to completely eradicate infectious agents.

In this respect, it has been accepted, in particular for PIDs, that chronic immune response due to an incomplete pathogen clearance may favor breakdown of peripheral tolerance. Additionally, given the critical role of CD21 and CD35 in the negative selection of self-reactive B cells Prodeus et al. The fate of self-reactive B cells within the bone marrow and peripheral lymphoid compartment is largely determined by the strength of signal mediated by BCR in response to antigen cross-linking Nemazee and Burki, ; Erikson et al.

To this regard, reports of a defective BCR activation are controversial. However, this defect was not confirmed by Henriquez et al. Very recently, two studies have shown the contribution of B cell intrinsic defects to the pathogenesis of autoimmunity in two different murine models.

Indeed, Becker-Herman et al. Based on this evidence, they demonstrated in mixed BM chimeras, in which only B cells lacked WASP expression, that the selective defect in B cells is sufficient for the generation of autoantibodies.

Overall, these findings highlight the contribution of B cells to the pathogenesis of autoimmunity in WAS and suggest that the B cell autonomous defect could represent a sufficient factor to break tolerance in WAS.

WAS is characterized by a very complex spectrum of cellular defects, many of which can predispose patients to the development of autoimmunity Figure 4. Figure 4. Schematic view of immunodeficiency and autoimmunity in WAS.

The impairment of both innate and adaptive immune systems is responsible of immunodeficiency blue box and autoimmunity red box in WAS. Immune cell defects described in WASP-deficient cells are shown in red. The incomplete pathogen clearance is sustained by cytoskeleton and functional defects of macrophages, DCs, T cells, B cells, and their defective interactions.


Autoimmunity in Wiskott–Aldrich syndrome: an unsolved enigma

Autoimmunity and Immunodeficiency View all 10 Articles. WASP is a cytoplasmic protein that regulates the formation of actin filaments in hematopoietic cells. Both cellular and humoral immune defects in WAS patients contribute to the onset of severe clinical manifestations, in particular microthrombocytopenia, eczema, recurrent infections, and a high susceptibility to develop autoimmunity and malignancies. Many groups have widely explored immune cell functionality in WAS partially explaining how cellular defects may lead to pathology. However, the mechanisms underlying the occurrence of autoimmune manifestations have not been clearly described yet.

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[Ileitis as Presentation of Lymphoma in Wiskott-Aldrich Syndrome]

Wiskott—Aldrich syndrome WAS is a rare X-linked recessive disease characterized by eczema , thrombocytopenia low platelet count , immune deficiency , and bloody diarrhea secondary to the thrombocytopenia. WAS occurs most often in males due to its X-linked recessive pattern of inheritance, affecting between 1 and 10 males per million. Spontaneous nose bleeds and bloody diarrhea are also common and eczema typically develops within the first month of life. Recurrent bacterial infections develop by three months. The majority of children with WAS develop at least one autoimmune disorder , and cancers mainly lymphoma and leukemia develop in up to a third of patients. WAS patients have increased susceptibility to infections, particularly of the ears and sinuses, and this immune deficiency has been linked to decreased antibody production and the inability of immune T cells to effectively combat infection.

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