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Immunodeficiency, Autoimmune Thrombocytopenia and Enterocolitis

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Immunodeficiency, Autoimmune Thrombocytopenia and Enterocolitis CASE REPORTS We report a child of consanguineous parentage (Figure Immunodeficiency, autoimmune thrombocytopenia 1A) who presented at 9 years with bruising and upper and enterocolitis caused by autosomal recessive gastrointestinal bleeding in association with profound deficiency of PIK3CD-encoded phosphoinositide immune-mediated thrombocytopenia. His thrombocy- 3-kinase δ topenia was refractory to corticosteroids, high dose immunoglobulin and splenectomy, culminating in an Phosphoinositide 3-kinase δ (PI3Kδ), a lipid kinase con- intracranial bleed requiring surgical evacuation. sisting of a catalytic (p110δ, encoded by PIK3CD) and a Immunosuppression was then intensified with regulatory subunit (p85, encoded by PIK3R1), generates cyclosporine, azathioprine and a course of the B-cell- the second messenger phosphatidylinositol (3,4,5)- depleting agent rituximab, with eventual platelet recov- trisphosphate (PIP3) in the plasma membrane of leuko- ery. However, over the next few months he developed 1 cytes downstream of antigen and cytokine receptors. first severe pneumonia followed by intractable diarrhea Signaling via PDK1, AKT, mTOR and downstream tar- and striking (~30%) weight loss. Endoscopy revealed gets such as FOXO1, contributes to the metabolic and enterocolitis, which histologically showed marked apop- transcriptional changes required for the expansion, differ- tosis of crypt epithelial cells, eosinophil and neutrophil entiation and effector function of lymphocytes.1 infiltration, crypt distortion and crypt abscess formation, Activating germline mutations in PIK3CD cause the with increased CD3+ cells but a paucity of B cells and immune dysregulatory disease activated PI3Kδ syndrome plasma cells in the lamina propria (Figure 1B, C). Viral (APDS), usually presenting with recurrent sinopulmonary inclusion bodies were visible, indicating active infections in childhood, herpes virus infections and CD4+ cytomegalovirus (CMV) replication in the gut, accompa- lymphopenia, underscoring the important role of bal- nied by CMV viremia (1.8x104 copies/mL); norovirus 1,2 anced p110δ activity in human adaptive immunity. genogroup 2 RNA was also detected in the stool. Flow Ablation of p110δ in mice leads to aberrant T-cell cytometric examination of peripheral blood revealed responses and intestinal inflammation.3,4 In humans, largely normal T-cell numbers, modestly reduced naïve T immune dysregulation including severe colitis is present cells, unexceptional T cell mitogenic responses and in many cancer patients who are treated with the p110δ- detectable FOXP3-positive regulatory T cells (Tregs) specific inhibitor idelalisib.5 Recently, one patient with (Online Supplementary Table 1 and Online Supplementary autosomal recessive deficiency of p85 6 and two patients Figure 1). Peripheral blood was enriched for a 7 + with loss of function mutations in p110δ have been effector/memory CD8 T cells, which expressed high lev- described who developed humoral immunodeficiency els of the transcription factor TBET and perforin (Figure and colitis. 1D, E). B cell numbers were low with no class-switched AB C DE FG Figure 1. PIK3CD mutation in a patient with immunodeficiency and immune dysregulation. (A) Pedigree. (B) Hematoxylin & eosin staining showing colitis and crypt abscess formation. (C) Immunostaining for CD3 (gold) and CD20 (purple); P1, patient; HD, healthy donor. (D) CCR7 and CD45RA staining and quantifica- tion of memory CD8+ cells among CD25-CD8+ cells. (E) Expression of perforin and transcription factor TBET in naïve and memory CD8+ T cells. (F) Sanger sequencing confirming frameshift deletion plus 2bp insertion. (G) p110δ schematic showing p.Q170Vfs*41 and previously reported mutations. haematologica 2019; 104:e483 CASE REPORTS memory B cells and subnormal immunoglobulin levels disease, indicating chronic immune-mediated inflamma- (IgG 2.5g/L and IgM 0.25g/L), consistent with prior ritux- tion. imab therapy and/or a primary B-cell abnormality (Online Hematopoietic stem cell transplantation (HSCT) was Supplementary Table 1). therefore performed as a potentially curative procedure. The patient was treated with total parenteral nutrition After reduced intensity conditioning (fludarabine 150 and an empiric combination of anti-inflammatory mg/m2, melphalan 140mg/m2, alemtuzumab 0.6mg/kg), (mesalazine) and antiviral (ganciclovir, foscarnet) therapy, the patient received bone marrow containing 6.9x106 but continued with torrential diarrhea (3L/day) until the CD34+ cells/kg from an 11/12-matched CMV+ve unrelat- addition of immunosuppression (corticosteroid, ed donor. Cotrimoxazole, foscarnet, liposomal ampho- cyclosporine, infliximab). Clinical improvement was tericin, and intravenous immunoglobulin were adminis- accompanied by amelioration of inflammatory changes tered as anti-infective prophylaxis with a combination of on repeat endoscopic examination. However, weaning of cyclosporine and mycophenolate mofetil to prevent graft immunosuppressive treatment led to a relapse of his gut versus host disease. Unfortunately we observed trans- A B C D Figure 2. Functional impact of PIK3CD mutation. (A) Immunoblotting of p110δ, AKT, pAKTT308, pERKT202/Y204, pS6S235/236 and beta-actin in control (HD) and patient + + (P1) CD4 and CD8 T lymphoblasts with and without CD3 stimulation. (B) PIP3 quantification before/after T-cell receptor (TCR) stimulation. (C) and (D) Extracellular acidification rate (Seahorse assay) and quantification of glycolysis in IL-2-stimulated T lymphoblasts of HD and P1 (C) or HD cells treated with ide- lalisib (D). Three independent experiments with 5-8 technical replicates each; values are plotted as mean of three time points for each injection and each repli- cate (**P<0.01 and ***P<0.001, Mann-Whitney U test). haematologica 2019; 104:e484 CASE REPORTS plant rejection with early autologous lymphoid reconsti- put of Tregs was normal, but Treg trafficking and sup- tution. We therefore proceeded to a second transplant, pressive activity including IL-10 secretion were dis- 4 using a more myeloablative conditioning regimen (treo- turbed. p110δ kinase-dead mice make weaker responses sulfan 42 mg/m2, fludarabine 150 mg/m2, alemtuzumab to antigen exposure than wild type mice, both in vivo and 1mg/kg) and peripheral blood stem cells (CD34+ dose in vitro,3,8 despite apparently normal proliferation and 5.3x106/kg) from an alternative partially mismatched metabolic reprogramming of CD8+ (11/12) unrelated donor. On this occasion he achieved T cells after stimulation of the TCR and the IL-2 9,10 + 100% donor chimerism including lymphoid reconstitu- receptor. Secretion of IFN-g by effector/memory CD8 tion and sustained remission of enterocolitis. Both trans- T cells was however significantly reduced by inhibitors of 11 9 plants were complicated by low level CMV viremia p110δ and AKT , consistent with the reduced produc- (<2000 copies/mL) and chronic norovirus genogroup 2 in tion of IFN-g in patient cells, and potentially relevant to stool. Despite the latter and prior history of prolonged viral susceptibility. This primary immunodeficiency thus gut failure, the patient required only 9 days’ parenteral highlights the central importance of regulated PI3Kδ nutrition in the wake of his first transplant and was oth- activity for immune homeostasis and protective immuni- erwise managed with nasogastric feeding and later diet. ty in humans as in mice. His 2nd transplant was also complicated by herpes sim- Germline autosomal recessive deficiency of PIK3CD plex virus (fever, viraemia, herpetic skin lesion – managed has recently been reported in a total of three kindreds with high dose IV acyclovir) and an asymptomatic peri- (Online Supplementary Table 3), though two siblings had a cardial effusion as well as mild pancreatitis (max amylase second concurrent immune disorder, complicating inter- 600 U/L) which resolved with conservative management. pretation of their phenotype.7,12,13 Of the remaining four Six months after the transplant, the patient returned to patients, all presented with hypogammaglobulinemia the Middle East in a stable condition without signs of and recurrent sinopulmonary infections, some including enterocolitis or infection and was lost to follow-up. severe and opportunistic pneumonias. Immune dysregu- Suspecting a monogenic immune disorder, we later car- latory phenomena were also frequent, including inflam- ried out whole exome sequencing of the patient’s genom- matory bowel disease, autoimmune hepatitis and ic DNA and found the private homozygous frameshift juvenile idiopathic arthritis. Their management involved variant c.703_723delinsGT in PIK3CD, confirmed by immunoglobulin replacement and antimicrobial therapy Sanger sequencing (Figure 1F). The 21bp deletion cou- for acute infections, together with anti-inflammatory pled to a two bp insertion in exon 5 introduces a prema- (mesalazine) or immunosuppressive (steroids and 6-mer- ture stop codon (p.Q170Vfs*41) (Figure 1G). Rare (<0.001 captopurine) therapy where indicated for autoimmune allele frequency) variants of unknown significance in complications.7,12,13 Although B- and NK-cell numbers other immune-related genes were excluded on the basis were very low in some patients, others had normal of poor fit to previously reported phenotypes (TCIRG1, counts and standard laboratory measures of T cell num- KDM6A, PLCG2) or autosomal recessive inheritance ber and function were generally unremarkable. Therefore (ACP5, STK4), respectively (Online Supplementary Table a high index
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