Inborn errors of immunity (primary immunodeficiencies): Classification

INTRODUCTION — Inborn errors of immunity (IEI; primary immunodeficiencies [PIDs]) encompass a group of nearly 500 inherited disorders, often due to single-gene mutations, that result in the specific impairment of normal immune development and function [1]. While individually rare, in aggregate, the prevalence of these conditions is approximately 1 in 1000 to 5 in 1000. The clinical presentation of IEI is variable and includes severe or unusual infections, autoimmune and autoinflammatory diseases, and malignancies [2]. The classification scheme provides a clinically oriented strategy for disease categorization to facilitate a thoughtful approach to patients.

Genetic testing in patients with a suspected IEI is reviewed in detail separately. (See "Genetic testing in patients with a suspected primary immunodeficiency or autoinflammatory syndrome".)

KEY POINTS — There are several key points to remember with regard to IEI and classification [1]. Infections signaling immunodeficiency can be of a single type (ie, papillomavirus or Epstein-Barr virus [EBV]). In addition, autoimmunity and autoinflammation are increasingly recognized as signs of IEI. The tables in the International Union of Immunological Societies (IUIS) classification attempt to reflect common presentations associated with each gene defect. However, there are many instances where different pathogenic variants in a single gene (eg, recombination-activating 1 [RAG1]) cause unique phenotypes; defects in different genes have a similar phenotype due to convergence on a shared critical pathway (eg, the severe combined immunodeficiency [SCID] genes); or the identical mutation is expressed differently, even in a single family. Furthermore, pathogenic variants can be somatic or mosaic and can present differently than germline variants. Thus, the categorization described below represents the broadest outline of the clinical approach to patients.

CLASSIFICATION — The expert committee of the International Union of Immunological Societies (IUIS) has classified IEI into nine categories of conditions based upon the segment of the immune system that is affected since 1999 [1]. A 10^th category comprises autoantibody mimics of IEI and somatic variants that also mimic the germline Mendelian conditions. Each category of IEI is characterized by unique types of infections, autoimmunity, and/or inflammation. Patients with antibody deficiency, for example, typically present with bacterial respiratory tract infections, while terminal complement deficiencies are characterized by recurrent meningitis from Neisseria species. The major IUIS categories of IEI, the number of genes described in each category, characteristics of each category, and representative examples are summarized in the table (table 1). Each individual category is discussed below in greater detail.

I. Immunodeficiencies affecting cellular and humoral immunity — Category I of the IUIS classification includes immunodeficiencies that affect both cellular and humoral immunity (table 2) (see "The adaptive cellular immune response: T cells and cytokines" and "The adaptive humoral immune response"). This group includes two subcategories: severe combined immunodeficiencies (SCID), defined by CD3 T cell lymphopenia, and combined immunodeficiencies (CIDs) without associated or syndromic features that are generally less profound than SCID. CID with associated or syndromic features is classified as a separate category. (See 'II. Combined immunodeficiencies with associated or syndromic features' below.)

●SCID defined by CD3 T cell lymphopenia (CD3+ T cells <300/microL):

•CD19 normal – SCID T-B+ (eg, X-linked SCID due to common gamma chain deficiency, Janus kinase 3 [JAK3] deficiency):

-(See "Severe combined immunodeficiency (SCID): An overview".)

-(See "Severe combined immunodeficiency (SCID): Specific defects".)

-(See "X-linked severe combined immunodeficiency (X-SCID)".)

-(See "Severe combined immunodeficiency (SCID) with JAK3 deficiency".)

-(See "CD3/T cell receptor complex disorders causing immunodeficiency".)

•CD19 low – SCID T-B- (eg, recombination-activating gene [RAG] 1/2 deficiency, adenosine deaminase [ADA] deficiency):

-(See "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis" and "T-B-NK+ SCID: Management".)

-(See "Adenosine deaminase deficiency: Pathogenesis, clinical manifestations, and diagnosis" and "Adenosine deaminase deficiency: Treatment and prognosis".)

●CIDs without associated or syndromic features that are generally less profound than SCID (eg, hyperimmunoglobulin M [hyper-IgM] syndrome due to cluster of differentiation [CD] 40 ligand deficiency, zeta chain-associated protein 70 [ZAP-70] deficiency):

•(See "Combined immunodeficiencies: An overview".)

•(See "Combined immunodeficiencies: Specific defects".)

•(See "Hyperimmunoglobulin M syndromes".)

•(See "ZAP-70 deficiency".)

•(See "CD3/T cell receptor complex disorders causing immunodeficiency".)

•(See "Idiopathic CD4+ lymphocytopenia".)

T cells represent the major component of the cellular immune system and are critical for defense against viral and fungal infections. Patients with T cell immunodeficiencies can have combined (T cell plus B cell/antibody) defects due to impaired T cell "help" required for generation of antibodies from B cells (B cell positive) or due to defects in the B cells themselves (B cell negative). (See "The adaptive cellular immune response: T cells and cytokines".)

Patients with T cell defects can present with viral, fungal, and/or bacterial infections, including opportunistic infections (eg, Pneumocystis jirovecii pneumonia) and infections from live vaccinations (eg, measles, mumps, and rubella [MMR] and varicella). The most severe example of T cell/CID is SCID. Patients with this condition are born with almost no T cells. Although many patients with SCID have B cells, antibody production is absent because there is no T cell help. Patients present within the first few months of life with life-threatening infections. Without curative therapy (hematopoietic cell transplantation or gene therapy), patients typically die from overwhelming infection before one year of age [3-5]. CIDs are somewhat arbitrarily distinguished from SCID in that they typically do not lead to death in the first year of life and typically have higher T cell numbers and T cell function compared with SCID. Newborn screening to detect very low T cells now exists in most of the United States and several other countries. (See "Severe combined immunodeficiency (SCID): An overview", section on 'Clinical manifestations' and "Recognition of immunodeficiency in the first three months of life" and "Hematopoietic cell transplantation for severe combined immunodeficiencies" and "Hematopoietic cell transplantation for non-SCID inborn errors of immunity" and "Overview of gene therapy for inborn errors of immunity" and "Newborn screening for inborn errors of immunity".)

The CID group is the most diverse, with global lymphocyte dysfunction, T cell-specific alterations that secondarily impact the B cells, and dysfunction of pathways intrinsic to lymphocytes but also impacting additional cell types. Although T cell numbers are generally low and clinical assessment of these represents a useful screening test, several CIDs do not have low T cell numbers (ras homolog family member H [RHOH]; mucosa-associated lymphoid tissue 1 paracaspase [MALT1]; caspase recruitment domain family member 11 [CARD11]; B cell CLL/lymphoma 10 immune signaling adaptor [BCL10]; interleukin 21 [IL21]; interleukin 21 receptor [IL21R]; tumor necrosis factor receptor superfamily, member 4 [TNFRSF4]; inhibitor of nuclear factor kappa B kinase subunit beta [IKBKB]; mitogen-activated protein kinase kinase kinase 14 [MAP3K14]; REL proto-oncogene, nuclear factor kappa B [NF-kB] subunit [REL]; RELB proto-oncogene, NF-kB subunit [RELB]; RELA proto-oncogene, NF-kB subunit [RELA]; moesin [MSN]; transferrin receptor [TFRC]; IKAROS family zinc finger 2 [IKZF2]; component of inhibitor of NF-kB kinase complex [CHUK]) or have T cells that decline over time. This group is also characterized by high rates of autoimmunity.

One example of this group is DOCK8 deficiency. Dedicator of cytokinesis 8 (DOCK8) is involved in actin assembly and branching, akin to the Wiskott-Aldrich syndrome protein (WASP). Both DOCK8 deficiency and Wiskott-Aldrich syndrome often presents with severe eczema and frequent infectious complications, such as staphylococcal infections, molluscum, and herpes. Later in life, the infections dominate the picture, and pneumonia becomes a common manifestation. Laboratory features are a very high immunoglobulin E (IgE), low immunoglobulin M (IgM), and eosinophilia, with declining T cell counts over time. (See "Combined immunodeficiencies: Specific defects", section on 'DOCK8 deficiency'.)

Initial screening should include enumeration of T cell numbers by flow cytometry (CD3, CD4, and CD8) and assessment of T cell function by testing proliferation to mitogens (proteins that stimulate T cell division), keeping in mind that T cell numbers can be normal in several forms of CID. (See "Laboratory evaluation of the immune system", section on 'Defects in cellular immunity' and "Flow cytometry for the diagnosis of inborn errors of immunity".)

Patients with human immunodeficiency virus (HIV) infections (a secondary T cell immunodeficiency) can present similarly to patients with primary T cell immunodeficiency. (See "Acute and early HIV infection: Clinical manifestations and diagnosis".)

II. Combined immunodeficiencies with associated or syndromic features — This heterogeneous category includes nine subgroups of genetic syndromes with unique clinical features and well-characterized underlying immune defects (table 3) (see "Syndromic immunodeficiencies"):

●Congenital thrombocytopenia – Disorders in this subcategory are characterized by CID with low platelets as a key clinical feature. Both Wiskott-Aldrich syndrome (WAS) and WAS protein-interacting protein (WIP) deficiency are characterized by thrombocytopenia with small platelets, bloody diarrhea, and eczema. Patients with actin-related protein 2/3 complex, subunit B (ARPC1B) deficiency (MIM #617718) have mild thrombocytopenia with normal-sized platelets, colitis, and vasculitis [6]. (See "Wiskott-Aldrich syndrome".)

●DNA repair defects other than forms of SCID in category I – Effective deoxyribonucleic acid (DNA) repair is essential for V(D)J recombination to generate T cell/B cell diversity and for effective class-switch recombination [7]. DNA repair defects can result in both T and B cell abnormalities. In addition to a CID phenotype, many of these conditions are characterized by other clinical features such as intrauterine growth restriction (IUGR), facial dysmorphisms, and increased radiosensitivity:

•(See "Ataxia-telangiectasia".)

•(See "Bloom syndrome".)

•(See "Nijmegen breakage syndrome".)

•(See "Syndromic immunodeficiencies", section on 'ICF syndrome'.)

●Thymic defects with additional congenital anomalies – T cell precursors require thymic tissue to complete development into mature functional T cells. Genetic disorders that result in impaired development of the thymus can result in CID. One of the most common (1:3000 live births) and well-characterized syndromes with underlying immunodeficiency is DiGeorge (22q11.2 deletion) syndrome. This syndrome is characterized by structural heart defects, hypoparathyroidism (resulting in hypocalcemia), characteristic facial features, and T cell immunodeficiency due to impaired development of the thymus [8]. Approximately 10 percent of patients with 22q11.2 deletion syndrome also have antibody deficiency. CHARGE (coloboma of the eye, heart anomalies, choanal atresia, retardation, genital and ear anomalies) syndrome due to pathogenic variants in the chromodomain helicase DNA-binding protein 7 (CHD7) gene can present similarly to patients with 22q11.2 deletion, but they also suffer from eye colobomas, choanal atresia, and ear abnormalities [9].

•DiGeorge/22q11.2 deletion syndrome and CHARGE syndrome:

-(See "DiGeorge (22q11.2 deletion) syndrome: Epidemiology and pathogenesis".)

-(See "DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis".)

-(See "DiGeorge (22q11.2 deletion) syndrome: Management and prognosis".)

•(See "Syndromic immunodeficiencies", section on 'Deletions of chromosome region 10p13-p14'.)

●Immunoosseous dysplasias – These disorders are characterized by CID features with skeletal abnormalities. Patients with cartilage-hair hypoplasia have short-limbed dwarfism with metaphyseal dysostosis. Patients with Schimke immunoosseous dysplasia have short stature, spondyloepiphyseal dysplasia, and IUGR:

•(See "Cartilage-hair hypoplasia".)

•(See "Syndromic immunodeficiencies", section on 'Schimke immunoosseous dysplasia'.)

•(See "Syndromic immunodeficiencies", section on 'Roifman syndrome'.)

●Hyper-IgE syndromes (HIES) – These disorders are all characterized by CID and elevated IgE. Signal transducer and activator of transcription (STAT) 3 deficiency (autosomal dominant hyper-IgE syndrome) is characterized by eczema, hyperextensible joints, retained primary teeth, coarse facial features, and minimal trauma fractures. Patients with Netherton syndrome have congenital ichthyosis, bamboo hair, and increased atopy. Patients with phosphoglucomutase 3 (PGM3) deficiency have severe atopy and autoimmunity:

•(See "Autosomal dominant hyperimmunoglobulin E syndrome".)

•(See "Netherton syndrome".)

●Defects of vitamin B12 and folate metabolism – Congenital defects in B12 and folate metabolism can result in a CID that is responsive to nutritional supplementation. Untreated patients suffer from intellectual disability. (See "Methylmalonic acidemia", section on 'Transcobalamin II deficiency'.)

●Anhidrotic ectodermal dysplasia with immunodeficiency – These disorders are characterized by CID and ectodermal dysplasia resulting in variable abnormal skin, conical teeth, and sparse hair. (See "Ectodermal dysplasias", section on 'Ectodermal dysplasia and immunodeficiency'.)

●CID due to calcium channel defects – Lymphocyte activation after antigen stimulation is mediated by calcium entry into the cell through Ca2+ release-activated Ca2+ (CRAC) channels. Defective activation of CRAC channels results in impaired lymphocyte activation and a CID phenotype. Patients also suffer from hypotonia and dental enamel abnormalities.

●Other defects:

•Purine nucleoside phosphorylase [PNP] deficiency – PNP is normally involved in the purine salvage pathway. PNP deficiency leads to an accumulation of intracellular deoxyguanosine triphosphate (dGTP), a metabolite that is toxic to lymphocytes. This disorder is characterized by CID, neurologic impairment, hemolytic anemia, and hypouricemia. (See "Purine nucleoside phosphorylase deficiency".)

•STAT5b deficiency – STAT5b is involved in the intracellular signaling cascade of interleukin (IL) 2, interferon (IFN) gamma, and growth hormone. This disorder is characterized by CID, growth hormone-insensitive dwarfism, autoimmunity, and facial dysmorphisms.

III. Predominantly antibody deficiencies — Category III of the IUIS classification comprises the predominantly antibody deficiencies, which represent the most common type of immunodeficiency (table 4). (See "Primary humoral immunodeficiencies: An overview".)

B cells differentiate into plasma cells that produce antibodies or immunoglobulins such as immunoglobulin G (IgG), immunoglobulin A (IgA), and IgM [10]. Antibodies can bind and opsonize pathogens to facilitate phagocytosis (bacteria opsonized by antibodies are phagocytosed 50-fold more efficiently by neutrophils) and activate complement proteins. Antibodies also represent an important part of our immune memory, something we take great advantage of in the form of vaccinations. As an example, when a patient receives a tetanus vaccine, long-lasting tetanus antibodies are produced that remain in circulation for many years and help prevent disease. (See "The adaptive humoral immune response".)

Patients with antibody deficiency commonly present with recurrent bacterial infections of the upper and lower respiratory tracts (ear infections, sinus infections, and pneumonia) from encapsulated bacteria such as Streptococcus pneumoniae [11]. However, more invasive bacterial infections such as sepsis, meningitis, and osteomyelitis can occur [12,13].

There are four subtypes in this category:

●Agammaglobulinemia with profoundly decreased or absent B cells – This category includes genetic defects that result in complete arrest of B cell development such as X-linked and autosomal recessive agammaglobulinemia. (See "Agammaglobulinemia".)

●B cells >1 percent, common variable immunodeficiency (CVID) phenotype – This category includes patients with a CVID phenotype (severe reduction in at least two serum immunoglobulin isotypes or low numbers of B cells) with either no gene defect specified or single gene defects such as phosphatidylinositol 3-kinase, catalytic, delta (PIK3CD) gain of function, CD19 deficiency, or nuclear factor kappa B1 (NFKB1) deficiency. As for other B cell defects, most patients have infections, but a significant proportion do not and present with immune thrombocytopenia (ITP) or hemolytic anemia, with or without marked lymphoid hyperplasia:

•(See "Pathogenesis of common variable immunodeficiency".)

•(See "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults".)

•(See "Treatment and prognosis of common variable immunodeficiency".)

•(See "Common variable immunodeficiency in children".)

●Severe reduction in serum IgG and IgA with normal or elevated IgM, hyper-IgM – Patients in this category have severe reduction in serum IgG and IgA with normal to elevated IgM and normal numbers of B cells. (See "Hyperimmunoglobulin M syndromes".)

●Isotype, light chain, or functional deficiencies with generally normal numbers of B cells – This category includes defects characterized by specific deficiencies in immunoglobulin levels or impaired specific antibody response:

•(See "IgG subclass deficiency".)

•(See "Specific antibody deficiency".)

•(See "Selective IgA deficiency: Clinical manifestations, pathophysiology, and diagnosis" and "Selective IgA deficiency: Management and prognosis".)

•(See "Selective IgM deficiency".)

•(See "Transient hypogammaglobulinemia of infancy".)

•Gain-of-function pathogenic variants in CARD11 result in B cell expansion with NFkB and T cell anergy (BENTA) syndrome. Patients have poor vaccine responses and develop splenomegaly and lymphadenopathy. (See "Primary humoral immunodeficiencies: An overview", section on 'Isotype, light chain, or functional deficiencies with generally normal numbers of B cells'.)

Initial screening for suspected antibody deficiency should include measurement of quantitative immunoglobulins (IgG, IgA, and IgM) and vaccine titers to immunizations such as tetanus, diphtheria, and pneumococcus. (See "Laboratory evaluation of the immune system", section on 'Antibody deficiency and defects' and "Assessing antibody function as part of an immunologic evaluation".)

IV. Diseases of immune dysregulation — This category of immunodeficiencies is characterized by defects in self-tolerance (central or peripheral) resulting in autoimmune disease with or without recurrent infections (table 5) [14]. There are seven subgroups:

●Familial hemophagocytic lymphohistiocytosis (FHL) syndromes – Patients in this category develop recurrent life-threatening episodes of hemophagocytic lymphohistiocytosis (HLH) with fever and hepatosplenomegaly. Immune testing reveals reduced or absent natural killer (NK) and cytotoxic T lymphocyte (CTL) activity. Examples in this category include perforin, Munc13-4, syntaxin 11, and Munc18-2 deficiencies.

●FLH with hypopigmentation – Patients in this category develop recurrent episodes of life-threatening HLH but also have skin or hair hypopigmentation. Examples in this category include Chediak-Higashi syndrome, Griscelli syndrome type 2, and Hermansky-Pudlak syndrome type 2:

•(See "Chediak-Higashi syndrome".)

●Regulatory T cell (Treg) defects (eg, IPEX) – Tregs play a critical role in peripheral tolerance by suppressing autoreactive T cells. Reduced or impaired function of Tregs results in systemic autoimmunity. Examples in this category include IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked), CD25 deficiency, and cytotoxic T lymphocyte-associated antigen 4 (CTLA4) deficiency:

•(See "IPEX: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked".)

•(See "IPEX: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked", section on 'IPEX-like syndromes'.)

•(See "Autoimmune lymphoproliferative syndrome (ALPS): Clinical features and diagnosis", section on 'CTLA-4 haploinsufficiency with autoimmune infiltration (CHAI) disease'.)

●Autoimmunity with or without lymphoproliferation (eg, autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy [APECED]). (See "Chronic mucocutaneous candidiasis", section on 'Autoimmune regulator deficiency'.)

●Immune dysregulation with colitis – Patients develop severe, early-onset inflammatory bowel disease (IBD; Crohn disease or ulcerative colitis), even as early as infancy. Examples in this category include IL-10, IL-10Ra, and IL-10Rb deficiencies. (See "Clinical presentation and diagnosis of inflammatory bowel disease in children", section on 'Very early-onset inflammatory bowel disease'.)

●Autoimmune lymphoproliferative syndrome (ALPS):

•(See "Autoimmune lymphoproliferative syndrome (ALPS): Epidemiology and pathogenesis".)

•(See "Autoimmune lymphoproliferative syndrome (ALPS): Clinical features and diagnosis".)

•(See "Autoimmune lymphoproliferative syndrome (ALPS): Management and prognosis".)

●Susceptibility to Epstein-Barr virus (EBV) – Patients in this category have a unique susceptibility to EBV infections that can lead to lymphoproliferation (eg, IL-2-induced T cell kinase [ITK], magnesium transporter 1 [MAGT1], and protein kinase C delta [PRKCD] deficiencies) or HLH (eg, X-linked lymphoproliferative disease due to pathogenic variants in Src homology 2 domain protein 1A [SH2D1A] or X-linked inhibitor of apoptosis [XIAP]). (See "X-linked lymphoproliferative disease".)

This category is often the most difficult to define clinically and to diagnose without extensive sequencing since there is significant phenotypic overlap between different genetic causes, evolution of features over time, and phenotypic heterogeneity, even in the same kindreds. Early-onset autoimmunity, autoimmunity that involves multiple organs, a strong family history of autoimmunity, autoimmunity in combination with susceptibility to infection, or significant lymphoproliferation all suggest an immune dysregulation defect. (See "Autoimmunity in patients with inborn errors of immunity/primary immunodeficiency".)

V. Congenital defects of phagocyte number, function, or both — Phagocytes such as neutrophils act as a first line of defense to protect the body from harmful bacteria and fungi by ingestion and destruction of these pathogens by activation of proteolytic enzymes. The fifth IUIS category includes congenital defects of phagocyte number or function and has four subgroups (table 6) (see "Primary disorders of phagocyte number and/or function: An overview"):

●Congenital neutropenia – Patients have severe congenital neutropenia and infections but no other syndromic features. Examples include elastase deficiency, HCLS1-associated protein X-1 (HAX1) deficiency, X-linked neutropenia, glucose-6-phosphatase catalytic subunit 3 (G6PC3) deficiency, and glycogen storage disease type 1b. (See "Congenital neutropenia".)

●Defects of motility – Patients have severe congenital neutropenia and infections but also have syndromic disease features such as dysmorphisms, developmental delay, and other nonimmune clinical features. Examples include leukocyte adhesion deficiency, Shwachman-Diamond syndrome, and cystic fibrosis:

•(See "Leukocyte-adhesion deficiency".)

•(See "Neutrophil-specific granule deficiency".)

•(See "Shwachman-Diamond syndrome".)

•(See "Cystic fibrosis: Clinical manifestations and diagnosis".)

●Defects of respiratory burst – Patients suffer from recurrent infections due to reduced neutrophil oxidative burst as measured by a dihydrorhodamine 123 (DHR) assay. Examples include chronic granulomatous disease and glucose-6-phosphate dehydrogenase (G6PD) deficiency class I:

•(See "Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis" and "Chronic granulomatous disease: Treatment and prognosis".)

•(See "Genetics and pathophysiology of glucose-6-phosphate dehydrogenase (G6PD) deficiency" and "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency".)

●Other nonlymphoid defects – Patients in this category have phagocyte function that is defective, but neutrophil oxidative burst testing (DHR assay) is normal. Examples include GATA-binding protein 2 (GATA2) deficiency and pulmonary alveolar proteinosis:

•(See "Mendelian susceptibility to mycobacterial diseases: Specific defects", section on 'GATA2 deficiency (MonoMAC syndrome)'.)

•(See "Causes, clinical manifestations, and diagnosis of pulmonary alveolar proteinosis in adults" and "Treatment and prognosis of pulmonary alveolar proteinosis in adults" and "Pulmonary alveolar proteinosis in children".)

Patients with impaired phagocyte immunity present with bacterial and fungal skin, lung, and lymph node infections/abscesses. Phagocytic immunodeficiencies include defects of phagocyte number (eg, absent neutrophils in severe congenital neutropenia), defects of phagocyte function (eg, absent oxidative burst in chronic granulomatous disease), and defects of phagocyte migration to sites of infection (eg, leukocyte adhesion deficiency) [15]. Initial screening labs should include enumeration of neutrophils (absolute neutrophil count) and assessment of neutrophil function (oxidative burst analysis by DHR). (See "Primary disorders of phagocyte number and/or function: An overview" and "Laboratory evaluation of the immune system", section on 'Tests for phagocytic abnormalities'.)

VI. Defects in intrinsic and innate immunity — The adaptive immune system (which includes B cells/antibodies and T cells) is designed to recognize and eliminate very specific pathogens. One limitation of the adaptive immune system is the slow kinetics of the response. As an example, it can take three to four weeks to generate protective IgG antibodies following administration of an immunization. By contrast, the innate immune system is "armed" and ready to fight infection immediately by recognizing unique features of pathogens that are not present on host cells. (See "An overview of the innate immune system".)

NK cells are innate lymphocytes that protect the body from herpes virus (herpes simplex virus [HSV], varicella-zoster virus [VZV], EBV, and cytomegalovirus [CMV]) infections and also play a role in tumor surveillance. Patients with NK cell defects suffer from recurrent herpes virus infections and increased risk of malignancies [16]. Patients with this phenotype should be screened by enumeration of NK cells by flow cytometry and assessment of NK cell function. (See "Laboratory evaluation of the immune system", section on 'Natural killer cell defects' and "NK cell deficiency syndromes: Clinical manifestations and diagnosis" and "NK cell deficiency syndromes: Treatment".)

Toll-like receptors (TLRs) are innate receptors on the surface of eukaryotic cells that recognize viral and bacterial components such as cell walls, flagella, and double-stranded ribonucleic acid (RNA). Signaling through TLRs leads to production of cytokines such as tumor necrosis factor (TNF) alpha, IL-6, and IL-1, which trigger fever and inflammation. Patients with TLR defects such as IL-1 receptor-associated kinase 4 (IRAK4) or myeloid differentiation primary response 88 (MyD88) deficiency suffer from recurrent invasive bacterial infections but often demonstrate impaired fever and inflammatory response (minimally elevated C-reactive protein [CRP] or erythrocyte sedimentation rate [ESR]) despite severe infections [17]. There are specific assays available to test TLR pathway signaling. (See "Laboratory evaluation of the immune system", section on 'Toll-like receptor pathway defects'.)

Defects in intrinsic and innate immunity make up the sixth IUIS category, with nine subgroups (table 7):

●Mendelian susceptibility to mycobacterial disease (MSMD) – The clinical phenotype in this category can range from severe (eg, disseminated Bacillus Calmette-Guérin [BCG] and mycobacteria in patients with complete IFN-gamma receptor 1 or 2 deficiency) to moderate (eg, IL-12 and IL-23 receptor deficiency, IL-12p40 deficiency, and tyrosine kinase 2 [TYK2] deficiency):

•(See "Mendelian susceptibility to mycobacterial diseases: An overview".)

•(See "Mendelian susceptibility to mycobacterial diseases: Specific defects".)

●Epidermodysplasia verruciformis (HPV) – Patients suffer from recurrent cutaneous warts from human papillomavirus (HPV). Examples include Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome and epidermodysplasia verruciformis 1/2 (EVER1/EVER2) deficiency:

•(See "Epidermodysplasia verruciformis", section on 'Pathogenesis'.)

•(See "Epidermodysplasia verruciformis", section on 'WHIM syndrome'.)

●Predisposition to severe viral infection – This category of innate immune defects is characterized by severe viral infections such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), influenza, herpes, varicella, or cytomegalovirus infections and are primarily due to decreased production of type 1 interferons. Some patients have difficulty with vaccine strain viral infections. Examples include STAT1, STAT2, IFN regulatory factor 7 (IRF7), IFN-alpha receptor 2 (IFNAR2), TLR3, TLR7, and CD16 deficiencies:

•(See "Mendelian susceptibility to mycobacterial diseases: Specific defects", section on 'Dominant negative LOF STAT1 deficiency'.)

•(See "Toll-like receptors: Roles in disease and therapy", section on 'UNC93B1 deficiency, TLR3 mutations, TRIF deficiency, TRAF3 deficiency, and TBK1 deficiency'.)

•(See "NK cell deficiency syndromes: Clinical manifestations and diagnosis", section on 'FCGR3A defects'.)

●Herpes simplex encephalitis (HSE) – Patients develop HSE during primary infection with herpes simplex virus type 1 (HSV1). Routine immune screening tests are normal. Specific assays examining the TLR3 pathway are required (demonstrating marked decrease in the patient's fibroblasts to produce IFN-alpha and IFN-beta in response to HSV1 infection). Examples include TLR3, UNC93 homolog B1 (UNC93B1), and TNF receptor-associated factor 3 (TRAF3) deficiencies. (See "Toll-like receptors: Roles in disease and therapy", section on 'UNC93B1 deficiency, TLR3 mutations, TRIF deficiency, TRAF3 deficiency, and TBK1 deficiency'.)

●Predisposition to invasive fungal diseases – Patients have a unique predilection to invasive fungal infections, particularly of the central nervous system (eg, CARD9 deficiency). (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Differential diagnosis'.)

●Predisposition to mucocutaneous candidiasis – While Candida is common, unusually severe or persistent Candida infections can represent a defect in mucosal immunity. Examples of this category include STAT1 gain of function, IL-17F deficiency, and IL-17RA deficiency. (See "Chronic mucocutaneous candidiasis".)

●TLR signaling pathway deficiency with predisposition to invasive bacterial infections (pyogens) – Patients with defects in TLR signaling can suffer from invasive bacterial infections such as meningitis, sepsis, arthritis, osteomyelitis, and abscesses, often in the absence of fever. The predominant pathogens include S. pneumoniae, Staphylococcus aureus, and Pseudomonas aeruginosa. The susceptibility to infections can improve with age. (See "Toll-like receptors: Roles in disease and therapy".)

●Other IEI related to nonhematopoietic tissues – These disorders include forms of isolated congenial asplenia, acute necrotizing encephalopathy, osteopetrosis, and hidradenitis suppurativa that are due to genetic defects. Certain pathogenic variants can increase susceptibility to parasitic infections such as trypanosomiasis:

•(See "Skeletal dysplasias: Specific disorders", section on 'Autosomal-dominant osteopetrosis, type II'.)

•(See "Hidradenitis suppurativa: Pathogenesis, clinical features, and diagnosis", section on 'Associated factors'.)

•(See "Human African trypanosomiasis: Epidemiology, clinical manifestations, and diagnosis", section on 'Innate immunity'.)

●Other IEI related to leukocytes – These disorders include forms associated with fulminant viral hepatitis and Whipple disease.  

VII. Autoinflammatory disorders — Autoinflammatory disorders arise from overactivation of innate inflammatory pathways resulting in excessive release of proinflammatory cytokines that cause recurrent fever and tissue damage [18]. This category of disorders is suggested by a history of recurrent inflammation without evidence of other disorders (eg, cyclic neutropenia) or infections. Genetic testing can help to confirm the diagnosis. (See "The autoinflammatory diseases: An overview" and "Laboratory evaluation of the immune system", section on 'Advanced genomic studies for all forms of IEIs' and "Genetic testing in patients with a suspected primary immunodeficiency or autoinflammatory syndrome".)

This IUIS category includes three subgroups (table 8):

●Type 1 interferonopathies – This subset of conditions has an inflammatory pattern related to interferon production. These disorders often have neurologic features:

•Aicardi-Goutières syndromes, stimulator of IFN genes (STING) associated vasculopathy with onset in infancy (SAVI), and ubiquitin-specific peptidase 18 (USP18) deficiency (see "Autoinflammatory diseases mediated by interferon production and signaling (interferonopathies)")

•DNA polymerase alpha 1, catalytic subunit (POLA1) deficiency (see "Congenital and inherited hyperpigmentation disorders", section on 'X-linked reticulate pigmentary disorder')

•Pulmonary alveolar proteinosis due to 2'-5'-oligoadenylate synthetase 1 (OAS1) gain of function (see "Genetic disorders of surfactant dysfunction", section on 'Related disorders')

•Deficiency of adenosine deaminase 2 (DADA2) (see "Deficiency of adenosine deaminase 2 (DADA2)")

●Defects affecting the inflammasome – This category is characterized by dysregulated expression of classic proinflammatory cytokines such as TNF, IL-18, and IL-1-beta secretion. Patients suffer from recurrent episodes of fever, arthritis, arthralgia, rashes, and abdominal pain. Patients are at risk for developing amyloidosis and IBD. One of the most common examples of this category is familial Mediterranean fever (FMF) syndrome. This condition occurs due to mutations in the MEFV, pyrin innate immunity regulator (MEFV) gene, which causes excessive release of the inflammatory cytokine IL-1:

•(See "Familial Mediterranean fever: Epidemiology, genetics, and pathogenesis" and "Clinical manifestations and diagnosis of familial Mediterranean fever" and "Management of familial Mediterranean fever".)

•(See "Hyperimmunoglobulin D syndrome: Pathophysiology" and "Hyperimmunoglobulin D syndrome: Clinical manifestations and diagnosis" and "Hyperimmunoglobulin D syndrome: Management".)

•(See "Cryopyrin-associated periodic syndromes and related disorders".)

•(See "Autoinflammatory diseases mediated by miscellaneous mechanisms", section on 'PLAID/APLAID'.)

•(See "Autoinflammatory diseases mediated by inflammasomes and related IL-1 family cytokines (inflammasomopathies)", section on 'The NLRP1 inflammasome'.)

•(See "Autoinflammatory diseases mediated by inflammasomes and related IL-1 family cytokines (inflammasomopathies)", section on 'The NLRC4 inflammasome'.)

●Noninflammasome-related conditions – These conditions do not directly affect the function of the inflammasome and have diverse impacts on cell biology. As expected, they have varied clinical presentations, and fever is a less common manifestation than in the classical inflammasome-mediated conditions. Rash is more common in this group, and psoriasis is a common but not universal association:

•(See "Tumor necrosis factor receptor-1 associated periodic syndrome (TRAPS)".)

•PAPA (pyogenic arthritis, pyoderma gangrenosum, and acne), deficiency of IL-1RA (DIRA), and deficiency of the IL-36 receptor antagonist (DITRA) (see "Autoinflammatory diseases mediated by inflammasomes and related IL-1 family cytokines (inflammasomopathies)", section on 'Diseases related to other IL-1 family proteins')

•Otulipenia and Blau syndrome (see "Autoinflammatory diseases mediated by NFkB and/or aberrant TNF activity")

•(See "Autoinflammatory diseases mediated by interferon production and signaling (interferonopathies)", section on 'CANDLE'.)

•(See "Autoinflammatory diseases mediated by miscellaneous mechanisms", section on 'COPA syndrome'.)

•(See "Clinical manifestations, pathologic features, and diagnosis of subcutaneous panniculitis-like T cell lymphoma".)

•CARD14-mediated psoriasis (CAMPS) (see "Psoriasis in children: Epidemiology, clinical manifestations, and diagnosis", section on 'Risk factors')

•ADAM metallopeptidase domain 17 (ADAM17) deficiency and very-early-onset IBD (see "Genetic factors in inflammatory bowel disease", section on 'Very early onset IBD')

•Adaptor-related protein complex 1 subunit sigma 3 (AP1S3) deficiency with pustular psoriasis (see "Palmoplantar pustulosis: Epidemiology, clinical features, and diagnosis" and "Pustular psoriasis: Pathogenesis, clinical manifestations, and diagnosis")

•Chronic nonbacterial osteomyelitis (CNO)/chronic recurrent multifocal osteomyelitis (CRMO) (see "Chronic nonbacterial osteomyelitis (CNO)/chronic recurrent multifocal osteomyelitis (CRMO)")

•H syndrome (see "Congenital and inherited hyperpigmentation disorders", section on 'H syndrome')

•(See "Autoinflammatory diseases mediated by NFkB and/or aberrant TNF activity", section on 'Haploinsufficiency of A20'.)

VIII. Complement deficiencies — The complement arm of the immune system protects the body from bacterial pathogens by opsonizing bacteria and also forming a membrane attack complex to cause lysis of bacteria. Complement proteins also play a role in clearance of apoptotic cell debris, which can cause autoimmune inflammation. There are three main complement protein pathways: classical complement, alternative complement, and lectin pathway (figure 1 and table 9). (See "Overview and clinical assessment of the complement system" and "Complement pathways" and "Regulators and receptors of the complement system".)

Early classical complement component deficiencies (C1q, C1r, C1s, C2, C4, C3) present with systemic lupus erythematosus (SLE) and susceptibility to infections from encapsulated bacteria. Terminal classical complement component deficiencies (C5, C6, C7, C8, C9) present with a unique susceptibility to recurrent Neisseria meningitis [19].

Similar to terminal complement deficiency, alternative complement pathway defects due to properdin or factor D present with recurrent meningitis. A deficiency of factor H and factor I (both complement regulatory proteins) can cause a phenotype of recurrent atypical hemolytic uremic syndrome or neisserial susceptibility, depending upon the mutation.

Initial screening tests for complement deficiency include a CH50 (total hemolytic complement) and AH50 (measures total functional activity of the alternative pathway). The CH50 test screens the entire classical complement pathway from C1 to C9. A deficiency of any of the classical complement components would yield a CH50 test value near 0 (thus a normal CH50 essentially rules out any defects in C1 to C9) [19]. (See "Overview and clinical assessment of the complement system", section on 'Complement measurement' and "Laboratory evaluation of the immune system", section on 'Tests for complement defects'.)

Detailed epidemiology, pathogenesis, clinical presentation, evaluation, and management of specific complement deficiencies are discussed separately. (See "Inherited disorders of the complement system" and "Complement-mediated hemolytic uremic syndrome in children".)

IX. Bone marrow failure — The bone marrow failure syndromes (BMFS) comprise an array of conditions where one or more hematopoietic elements decline over time. They often manifest with macrocytic anemia, but there is a broad array of presenting manifestations. Although all patients will have characteristic bone marrow biopsy findings in time, the key features are not necessarily obvious at presentation. (See "Approach to the adult with pancytopenia" and "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis".)

Genetic defects that cause bone marrow failure make up the ninth IUIS category, with disorders that include (table 10):

●Fanconi anemia – The majority of patients with Fanconi anemia will have skeletal findings or other congenital malformations leading to the diagnosis. Bone marrow failure occurs at a median age of seven years, and nearly all patients have bone marrow failure by 40 years of age. Acute myeloid leukemia and solid tumors are common in this population. (See "Clinical manifestations and diagnosis of Fanconi anemia" and "Management and prognosis of Fanconi anemia".)

●Dyskeratosis congenita (DKC), myelodysplasia, defective telomere maintenance – Telomeres are structures at the ends of linear chromosomes that prevent the loss of genetic material that normally occurs with every cell division. Without proper telomere maintenance, cell senescence and apoptosis can occur, especially in highly proliferative cell types such as lymphocytes. In addition to bone marrow failure, patients can develop nail dystrophy, sparse hair, abnormal skin pigmentation, lung fibrosis, and enteropathy. X-linked, autosomal recessive, and autosomal dominant forms of DKC due to various gene defects have been described. (See "Dyskeratosis congenita and other telomere biology disorders".)

●Bone marrow failure syndromes (BMFS) – This category includes signal recognition particle 72-kD (SRP72) deficiency, which is associated with bone marrow failure and congenital nerve deafness, as well as bone marrow failure syndrome 5 (BMFS5; due to pathogenic variants in tumor protein p53 [TP53]), characterized by severe erythroid hypoplasia requiring transfusions, B cell deficiency, poor growth, microcephaly, developmental delay, and seizures. (See "Familial disorders of acute leukemia and myelodysplastic syndromes", section on 'Familial aplastic anemia/MDS with SRP72 mutation' and "Familial disorders of acute leukemia and myelodysplastic syndromes", section on 'Familial ALL due to TP53 mutation'.)

●Others – These disorders include myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy (MIRAGE) syndrome due to gain-of-function pathogenic variants in sterile alpha motif domain containing 9 (SAMD9), ataxia pancytopenia syndrome due to gain-of-function pathogenic variants in sterile alpha motif domain containing 9-like (SAMD9L), and Coats plus syndrome due to pathogenic variants in CST telomere replication complex component 1 (CTC1). (See "Familial disorders of acute leukemia and myelodysplastic syndromes", section on 'Monosomy 7 and SAMD9/SAMD9L mutations' and "Dyskeratosis congenita and other telomere biology disorders", section on 'Coats plus syndrome'.)

X. Phenocopies of inborn errors of immunity — This category includes disorders that mimic IEI. These disorders are either associated with somatic mutations rather than germline mutations or are associated with autoantibodies (table 11):

●Associated with somatic pathogenic variants:

•ALPS due to somatic pathogenic variants in Fas cell surface death receptor (FAS; ALPS-sFAS). (See "Autoimmune lymphoproliferative syndrome (ALPS): Epidemiology and pathogenesis".)

•Cryopyrinopathy due to somatic nucleotide-binding domain and leucine-rich repeat containing family, purine domain containing 3 (NLRP3) mosaicism. (See "Cryopyrin-associated periodic syndromes and related disorders", section on 'Diagnosis'.)

•Hypereosinophilic syndrome due to somatic gain-of-function pathogenic variants in STAT5b. Patients develop early-onset eosinophilia, atopic dermatitis, urticarial rash, diarrhea. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'T cell lymphocytic variants'.)

●Associated with autoantibodies:

•Severe SARS-CoV2 infection due to autoantibodies against type 1 interferons (IFN-alpha and IFN-omega).

•Chronic mucocutaneous candidiasis due to autoantibodies to IL-17 and/or IL-22. (See "Chronic mucocutaneous candidiasis".)

•Adult-onset MSMD with autoantibodies to IFN-gamma. (See "Mendelian susceptibility to mycobacterial diseases: An overview", section on 'Differential diagnosis'.)

•Recurrent staphylococcal skin infections due to autoantibodies to IL-6.

•Autoantibodies to granulocyte macrophage colony-stimulating factor (GM-CSF) can cause pulmonary alveolar proteinosis. (See "Causes, clinical manifestations, and diagnosis of pulmonary alveolar proteinosis in adults", section on 'Anti-GM-CSF titer'.)

•Acquired angioedema with autoantibodies to C1 inhibitor. (See "Acquired C1 inhibitor deficiency: Clinical manifestations, epidemiology, pathogenesis, and diagnosis", section on 'Antibodies to C1 inhibitor'.)

•Autoantibodies to factor H can cause atypical hemolytic uremic syndrome due to spontaneous activation of the alternative complement pathway. (See "Complement-mediated hemolytic uremic syndrome in children", section on 'Complement antibodies'.)

•Thymoma with hypogammaglobulinemia (Good syndrome) is characterized by anti-cytokine autoantibodies.

RESOURCES — There are several resources to provide guidance when considering the many IEI. A categorical listing is available as a cell phone app (PID Phenotypical Diagnosis for iOs devices or PID Classification for Android devices). The International Union of Immunological Societies (IUIS) list of IEI is updated every six months and can be downloaded from the IUIS website, Inborn Errors of Immunity (IEI) Committee page.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)

SUMMARY

●Classification overview – Nearly 500 inborn errors of immunity (IEI or primary immunodeficiencies [PIDs]) have been described. The International Union of Immunological Societies (IUIS) has classified these disorders into nine categories based upon the segment of the immune system that is affected, plus a 10^th category of IEI phenocopies (table 1). Each category is characterized by unique types of infections and clinical features that are useful for the selection of initial appropriate laboratory evaluation to help with diagnosis. (See 'Introduction' above and 'Classification' above and 'Resources' above.)

●Category I (combined immunodeficiencies without syndromic features) – Category I of the IUIS classification includes immunodeficiencies that affect both cellular and humoral immunity (combined immunodeficiencies [CIDs]) but that lack the additional defining syndromic features of the disorders included in category II (table 2). Patients with T cell defects can present with viral, fungal, and/or bacterial infections, including opportunistic infections (eg, Pneumocystis jirovecii pneumonia) and infections from live vaccinations (eg, measles, mumps, and rubella [MMR] and varicella). The most severe example is severe combined immunodeficiency (SCID), which presents in infancy. (See 'I. Immunodeficiencies affecting cellular and humoral immunity' above.)

●Category II (combined immunodeficiencies with syndromic features) – Category II is a heterogeneous group of CIDs with unique clinical features and well-characterized underlying immune defects (table 3). (See 'II. Combined immunodeficiencies with associated or syndromic features' above.)

●Category III (predominantly antibody deficiencies) – Category III of the IUIS classification comprises the predominantly antibody deficiencies, which represent the most common type of immunodeficiency (table 4). Patients with an antibody deficiency commonly present with recurrent bacterial infections of the upper and lower respiratory tracts (ear infections, sinus infections, and pneumonia) from encapsulated bacteria. (See 'III. Predominantly antibody deficiencies' above.)

●Category IV (diseases of immune dysregulation) – Category IV is often the most difficult to define clinically and to diagnose. This category of immunodeficiencies is characterized by defects in self-tolerance (central or peripheral) resulting in autoimmune disease or significant lymphoproliferation that may or may not be accompanied by recurrent infections (table 5). (See 'IV. Diseases of immune dysregulation' above.)

●Category V (defects of phagocyte number/function) – Category V includes congenital defects of phagocyte number and/or function (table 6). Phagocytes such as neutrophils act as a first line of defense to protect the body from harmful bacteria and fungi by ingestion and destruction of these pathogens by activation of proteolytic enzymes. Patients with impaired phagocyte immunity present with bacterial and fungal skin, lung, and lymph node infections/abscesses. (See 'V. Congenital defects of phagocyte number, function, or both' above.)

●Category VI (defects in intrinsic and innate immunity) – Category VI is a heterogeneous group of disorders caused by defects in intrinsic and innate immunity, including natural killer (NK) cells, Toll-like receptors (TLRs), various cytokines, and other signaling molecules (table 7). (See 'VI. Defects in intrinsic and innate immunity' above.)

●Category VII (autoinflammatory disorders) – Category VII includes the autoinflammatory disorders that arise from overactivation of innate inflammatory pathways resulting in excessive release of proinflammatory cytokines that cause recurrent fever and tissue damage (table 8). This category of disorders is suggested by a history of recurrent inflammation in the absence of other identifiable disorders or infections. (See 'VII. Autoinflammatory disorders' above.)

●Category VIII (complement deficiencies) – Category VIII comprises the complement deficiencies (table 9). Early classical complement component deficiencies (C1q, C1r, C1s, C2, C4, C3) present with systemic lupus erythematosus (SLE) and susceptibility to infections from encapsulated bacteria. Terminal classical complement component deficiencies (C5, C6, C7, C8, C9) present with a unique susceptibility to recurrent Neisseria meningitis. Alternative complement pathway defects due to properdin or factor D present with recurrent meningitis. A deficiency of factor H and factor I (both complement regulatory proteins) can cause a phenotype of recurrent atypical hemolytic uremic syndrome or neisserial susceptibility, depending upon the mutation. (See 'VIII. Complement deficiencies' above.)

●Category IX (defects that cause bone marrow failure) – Category IX includes genetic defects that cause bone marrow failure. In this category are found telomere defects, Fanconi anemia, and several conditions where bone marrow failure develops in association with clear immunologic dysfunction (table 10). (See 'IX. Bone marrow failure' above.)

●Category X (phenocopies of IEI) – Category X includes disorders that mimic IEI. These disorders are either associated with somatic mutations rather than germline mutations or are associated with autoantibodies (table 11). (See 'X. Phenocopies of inborn errors of immunity' above.)