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Key Points PI3Kδ (phosphoinositide 3-kinase-δ) is a key signal transduction node in cells of the immune system. This kinase complex is acutely activated in B cells and T cells after exposure to antigen and controls many aspects of lymphocyte development and differentiation, in part via the AKT, forkhead box O1 (FOXO1) and mechanistic target of rapamycin (mTOR) pathways. Rare loss-of-function mutations affecting PI3Kδ also cause immunodeficiency and immune-mediated pathologies, including colitis. The PI3Kδ inhibitor idelalisib frequently causes colitis at doses tested in leukaemia and lymphoma trials, possibly due to effects on regulatory T (T reg ) cells. Activated PI3Kδ syndrome (APDS; also called PASLI disease) is a newly described primary immunodeficiency caused by hyperactive PI3Kδ signalling and resultant T cell senescence and/or death and impaired antibody responses. APDS is generally characterized by recurrent sinopulmonary infections with structural lung damage, viraemia with herpes family viruses, lymphoproliferative disease and increased risk of B cell malignancies. Patients with APDS1 have a heterozygous mutation in PIK3CD , the gene encoding the p110δ catalytic subunit of PI3Kδ, whereas APDS2 patients have a heterozygous mutation in PIK3R1 , the gene encoding the p85α regulatory subunit of PI3Kδ. Both sets of mutations lead to higher intrinsic activity of PI3Kδ. To date, most patients with APDS have been treated with antibody replacement therapies and some have also been treated with the mTOR inhibitor rapamycin. In the future, PI3Kδ inhibitors may be used to treat these patients, possibly as the first example of targeted therapy against a hyperactive mutant kinase in primary immunodeficiency. Gain- and loss-of-function mutations in phosphoinositide 3-kinase-δ (PI3Kδ) result in a primary immunodeficiency syndrome termed APDS. Understanding the function of PI3Kδ in adaptive immune responses — from studies of mouse models of these mutations and from patients with APDS — provides new insights on how mutations in PI3Kδ promote immunodeficiencies. Primary immunodeficiencies are inherited disorders of the immune system, often caused by the mutation of genes required for lymphocyte development and activation. Recently, several studies have identified gain-of-function mutations in the phosphoinositide 3-kinase (PI3K) genes PIK3CD (which encodes p110δ) and PIK3R1 (which encodes p85α) that cause a combined immunodeficiency syndrome, referred to as activated PI3Kδ syndrome (APDS; also known as p110δ-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency (PASLI)). Paradoxically, both loss-of-function and gain-of-function mutations that affect these genes lead to immunosuppression, albeit via different mechanisms. Here, we review the roles of PI3Kδ in adaptive immunity, describe the clinical manifestations and mechanisms of disease in APDS and highlight new insights into PI3Kδ gleaned from these patients, as well as implications of these findings for clinical therapy.

Congenital athymia is an ultra-rare disease characterized by the absence of a functioning thymus. It is associated with several genetic and syndromic disorders including FOXN1 deficiency, 22q11.2 deletion, CHARGE Syndrome (Coloboma, Heart defects, Atresia of the nasal choanae, Retardation of growth and development, Genitourinary anomalies, and Ear anomalies), and Complete DiGeorge Syndrome. Congenital athymia can result from defects in genes that impact thymic organ development such as FOXN1 and PAX1 or from genes that are involved in development of the entire midline region, such as TBX1 within the 22q11.2 region, CHD7, and FOXI3. Patients with congenital athymia have profound immunodeficiency, increased susceptibility to infections, and frequently, autologous graft-versus-host disease (GVHD). Athymic patients often present with absent T cells but normal numbers of B cells and Natural Killer cells (T−B+NK+), similar to a phenotype of severe combined immunodeficiency (SCID); these patients may require additional steps to confirm the diagnosis if no known genetic cause of athymia is identified. However, distinguishing athymia from SCID is crucial, as treatments differ for these conditions. Cultured thymus tissue is being investigated as a treatment for congenital athymia. Here, we review what is known about the epidemiology, underlying etiologies, clinical manifestations, and treatments for congenital athymia.

Good syndrome is a rare adult-onset immunodeficiency characterized by thymoma and hypogammaglobulinemia. Its clinical manifestations are highly heterogeneous, ranging from various infections to autoimmunity. This study was to summarize patient characteristics, identify prognostic factors and define clinical subgroups of Good syndrome. A systematic literature review was conducted to include patients with Good syndrome identified in PubMed, Embase and Cochrane databases between January 2010 and November 2020. Logistic and Cox regressions were used to identify prognostic factors impacting outcomes. Clinical subgroups were defined by multiple correspondence analysis and unsupervised hierarchical clustering. A decision tree was constructed to characterize the subgroup placement of cases. Of 162 patients included in the current study, the median age at diagnosis was 58 years and 51% were male. Type AB was the most common histological subtype of thymoma, and infections as well as concurrent autoimmune disorders were identified in 92.6% and 51.2% patients, respectively. Laboratory workup showed typical findings of combined immunodeficiency. Thymoma status (odds ratio [OR] 4.157, confidence interval [CI] 1.219-14.177, = 0.023), infections related to cellular immunity defects (OR 3.324, 95% CI 1.100-10.046, = 0.033), infections of sinopulmonary tract (OR 14.351, 95% CI 2.525-81.576, = 0.003), central nerve system (OR 6.403, 95% CI 1.205-34.027, = 0.029) as well as bloodstream (OR 6.917, 95% CI 1.519-31.505, = 0.012) were independent prognostic factors. The 10-year overall survival was 53.7%. Cluster analysis revealed three clinical subgroups with distinct characteristics and prognosis (cluster 1, infections related to cellular immunity defects; cluster 2, infections related to other immunity defects; cluster 3, infections related to humoral and phagocytic immunity defects). A decision tree using infection types (related to humoral and cellular immunity defects) could place patients into corresponding clusters with an overall correct prediction of 72.2%. Infection type and site were the main prognostic factors impacting survival of patients with Good syndrome. We identified three subgroups within Good syndrome associated with distinct clinical features, which may facilitate the study of underlying pathogenesis as well as development of targeted therapy.

For seven decades, the pathophysiology of Good’s syndrome (GS) has remained a mystery, with few attempts to solve it. Initially described as an association between hypogammaglobulinemia and thymoma, controversy exists whether this is a unique disease, or a subgroup of Common Variable Immune Deficiency (CVID). Recently, some distinguishing aspects of both syndromes have come to light reflecting fundamental differences in their underlying pathophysiology. GS and CVID differ in demographic features and immune phenotype. GS is found almost exclusively in adults and is characterized by a significantly reduced or absence of peripheral B cells. In CVID, which also occurs in children, most patients have normal or slightly reduced peripheral B cells, with a distinguishing feature of low memory B cells. Similarly, differences in T cell dysregulation and manifestations of hematologic cytopenias may further distinguish GS from CVID. Knowledge of the clinical phenotype of this rare adult immune deficiency stems from individual case reports, retrospective, and cross-sectional data on a few cohorts with a limited number of well characterized patients. The understanding of pathophysiology in GS is hampered by the incomplete and inconsistent reporting of clinical and laboratory data, with a limited knowledge of its natural history. In this mini review, we discuss current state of the art data and identify research gaps. In order to resolve controversies and fill in knowledge gaps, we propose a coordinated paradigm shift from incidence reporting to robust investigative studies, addressing mechanisms of disease. We hope this novel approach sets a clear direction to solve the current controversies.

Activated phosphoinositide 3-kinase δ syndrome (APDS), also known as PASLI disease (p110d-activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency) are combined immunodeficiencies resulting from gain-of-function mutations in the genes ( and ) encoding the subunits of phosphoinositide 3-kinase δ (PI3Kδ) and were first described in 2013. These mutations result in the hyperactivation of the PI3K/AKT/mTOR/S6K signally pathways. In this mini-review we have detailed the current treatment options for APDS. These treatments including conventional immunodeficiency therapies such as immunoglobulin replacement, antibiotic prophylaxis, and hematopoietic stem cell transplant. We also discuss the more targeted therapies of mTOR inhibition with sirolimus and selective PI3Kδ inhibitors.

The deficiency of Adenosine Deaminase 2 (DADA2) is a new autoinflammatory disease characterised by an early onset vasculopathy with livedoid skin rash associated with systemic manifestations, CNS involvement and mild immunodeficiency. This condition is secondary to autosomal recessive mutations of CECR1 (Cat Eye Syndrome Chromosome Region 1) gene, mapped to chromosome 22q11.1, that encodes for the enzymatic protein adenosine deaminase 2 (ADA2). By now 19 different mutations in CECR1 gene have been detected. The pathogenetic mechanism of DADA2 is still unclear. ADA2 in a secreted protein mainly expressed by cells of the myeloid lineage; its enzymatic activity is higher in conditions of hypoxia, inflammation and oncogenesis. Moreover ADA2 is able to induce macrophages proliferation and differentiation; it’s deficiency is in fact associated with a reduction of anti-inflammatory macrophages (M2). The deficiency of ADA2 is also associated with an up-regulation of neutrophils-expressed genes and an increased secretion of pro-inflammatory cytokines. The mild immunodeficiency detected in many DADA2 patients suggests a role of this protein in the adaptive immune response; an increased mortality of B cells and a reduction in the number of memory B cells, terminally differentiated B cells and plasmacells has been described in many patients. The lack of the protein is associated with endothelium damage; however the function of this protein in the endothelial homeostasis is still unknown. From the clinical point of view, this disease is characterized by a wide spectrum of severity. Chronic or recurrent systemic inflammation with fever, elevation of acute phase reactants and skin manifestations (mainly represented by livedo reticularis) is the typical clinical picture. While in some patients the disease is mild and skin-limited, others present a severe, even lethal, disease with multi-organ involvement; the CNS involvement is rather common with ischemic or hemorrhagic strokes. In many patients not only the clinical picture but also the histopathologic features are undistinguishable from those of systemic polyarteritis nodosa (PAN). Of note, patients with an unusual phenotype, mainly dominated by clinical manifestations suggestive for an immune-disrective condition, have been described. Due to its rarity, the response to treatment of DADA2 is still anecdotal. While steroids can control the disease’s manifestations at high dosage, none of the common immunosuppressive drugs turned out to be effective. Biologic drugs have been used only in few patients, without a clear effectiveness; anti-TNF drugs are those associated to a better clinical response. Hematopoietic stem cells transplantation was effective in patients with a severe phenotype.

The key problem in human infectious diseases was posed at the turn of the 20th century: their pathogenesis. For almost any given virus, bacterium, fungus, or parasite, life-threatening clinical disease develops in only a small minority of infected individuals. Solving this infection enigma is important clinically, for diagnosis, prognosis, prevention, and treatment. Some microbes will inevitably remain refractory to, or escape vaccination, or chemotherapy, or both. The solution also is important biologically, because the emergence and evolution of eukaryotes alongside more rapidly evolving prokaryotes, archaea, and viruses posed immunological challenges of an ecological and evolutionary nature. We need to study these challenges in natural, as opposed to experimental, conditions, and also at the molecular and cellular levels. According to the human genetic theory of infectious diseases, inborn variants underlie life-threatening infectious diseases. Here I review the history of the field of human genetics of infectious diseases from the turn of the 19th century to the second half of the 20th century. This paper thus sets the scene, providing the background information required to understand and appreciate the more recently described monogenic forms of resistance or predisposition to specific infections discussed in a second paper in this issue.

Secondary antibody deficiencies (SADs) are a significant but frequently under-recognised group of acquired immunodeficiencies. They may arise in various clinical settings, including haematological malignancies, immunosuppressive therapies, and protein-losing conditions. SADs are associated with an increased risk of recurrent and severe infections, hospitalisation, and impaired quality of life. Despite this, diagnostic and treatment pathways remain inconsistent across healthcare settings and regions. Recent advances in the use of structured clinical data, including electronic health records and systematic laboratory assessments, show promise in facilitating earlier recognition of SADs. These approaches support more timely treatment decisions and promote consistent standards of care. Achieving improved outcomes for individuals with SADs will require broader consensus on diagnostic criteria, treatment thresholds, and access to specialist immunology services.

Secondary antibody deficiencies (SADs) are characterized by impaired humoral immunity, which can cause recurrent and severe infections. Several factors may contribute to SAD development, making it difficult to establish a clear etiological classification. This heterogeneity also leads to clinical variability, further complicating patient management and treatment strategies. Various diagnostic and therapeutic algorithms are often adapted from those used in primary antibody deficiencies, potentially resulting in under- or over-treatment. Key points include the decision to initiate Immunoglobulin Replacement Therapy (IgRT) and the duration of the treatment. Given the increasing prevalence of SADs and the limited availability of immunoglobulin products, it is important to clarify when IgRT should be started. In this review, we summarize and update the different etiologies of SADs and propose a diagnostic algorithm applicable regardless of the underlying cause. We also examine the possible treatment options and diagnostic tools that can assist in making the correct therapeutic choice.

Germline heterozygous gain-of-function (GOF) mutations of NFKBIA , encoding IκBα, cause an autosomal dominant (AD) form of anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID). Fourteen unrelated patients have been reported since the identification of the first case in 2003. All mutations enhanced the inhibitory activity of IκBα, by preventing its phosphorylation on serine 32 or 36 and its subsequent degradation. The mutation certainly or probably occurred de novo in 13 patients, whereas it was inherited from a parent with somatic mosaicism in one patient. Eleven mutations, belonging to two groups, were identified: (i) missense mutations affecting S32, S36, or neighboring residues (8 mutations, 11 patients) and (ii) nonsense mutations upstream from S32 associated with the reinitiation of translation downstream from S36 (3 mutations, 3 patients). Thirteen patients had developmental features of EDA, the severity and nature of which differed between cases. All patient cells tested displayed impaired NF-κB-mediated responses to the stimulation of various surface receptors involved in cell-intrinsic (fibroblasts), innate (monocytes), and adaptive (B and T cells) immunity, including TLRs, IL-1Rs, TNFRs, TCR, and BCR. All patients had profound B-cell deficiency. Specific immunological features, found in some, but not all patients, included a lack of peripheral lymph nodes, lymphocytosis, dysfunctional α/β T cells, and a lack of circulating γ/δ T cells. The patients had various pyogenic, mycobacterial, fungal, and viral severe infections. Patients with a missense mutation tended to display more severe phenotypes, probably due to higher levels of GOF proteins. In the absence of hematopoietic stem cell transplantation (HSCT), this condition cause death before the age of 1 year (one child). Two survivors have been on prophylaxis (at 9 and 22 years). Six children died after HSCT. Five survived, four of whom have been on prophylaxis (3 to 21 years post HSCT), whereas one has been well with no prophylaxis. Heterozygous GOF mutations in IκBα underlie a severe and syndromic immunodeficiency, the interindividual variability of which might partly be ascribed to the dichotomy of missense and nonsense mutations, and the hematopoietic component of which can be rescued by HSCT.