Primary immune deficiency diseases (PIDDs)

What is Primary immune deficiency diseases (PIDDs)?

What is Primary immune deficiency diseases (PIDDs)?

Primary immune deficiency diseases (PIDDs) are characterized by increased susceptibility to infections, often associated with autoimmunity and inflammation and an increased risk of malignancies because of impaired immune homeostasis and surveillance. Depending on the nature of the immune defect, the clinical presentation of PIDD may vary and may include recurrence of upper and lower respiratory tract infections, invasive bacterial infections, purulent lymphadenitis, skin or deep abscesses, infections sustained by poorly virulent or opportunistic pathogens (Pneumocystis jiroveci, cytomegalovirus, environmental mycobacteria, Cryptosporidium, Giardia lamblia), persistent or recurrent candidiasis, autoimmunity, increased susceptibility to malignancies, and association with typical signs of specific immunodeficiency syndromes.

With the exception of immunoglobulin (Ig) A deficiency, PIDDs are generally rare, with a prevalence of approximately 1:10,000 to 1:50,000. However, prompt recognition of PIDD is of importance, because diagnostic delay is associated with increased risk of death and of irreversible complications. Most forms of PIDD follow mendelian inheritance; however, some, for example, common variable immunodeficiency (CVID), have a multifactorial origin. In most cases, PIDDs present in childhood, but late presentations may occur or even predominate in some forms, such as CVID.

The diagnostic approach to PIDD is based on a detailed family and clinical history, physical examination and appropriate laboratory tests. Lymphopenia is characteristic of severe combined immune deficiency. Abnormalities of the neutrophil count can be observed in patients with disorders of neutrophil production (e.g., congenital neutropenia) or function (e.g., chronic granulomatous disease), respectively. Evaluation of serum immunoglobulin levels and of antibody responses to immunization antigens is important for patients with a history of recurrent infections. The clinical presentation and the results of these preliminary evaluations may prompt additional laboratory testing. For instance, patients with a profound hypogammaglobulinemia and a history of recurrent infections should be tested for the presence of circulating B lymphocytes (CD19+ or CD20+ cells), which are absent or markedly reduced in X-linked agammaglobulinemia. On the other hand, early presentation with severe and/or opportunistic infections, especially if associated with lymphopenia, should prompt enumeration of lymphocyte subsets. A severe reduction of circulating CD3+ T cells is typically observed in severe combined immune deficiency, and may be associated with defects of B and/or natural killer cells. Deep bacterial infections, or infections sustained by Aspergillus, require evaluation of neutrophil count and function, to identify patients with congenital neutropenia and chronic granulomatous disease, respectively. Invasive recurrent infections sustained by Neisseria species are an indication for assessing complement levels and function. On the other hand, complement component deficiencies may also lead to systemic lupus erythematosus-like features or to autoimmune disorders. Laboratory results should be compared to age-matched control values, as white blood cell counts, lymphocyte subsets, complement components and immunoglobulin levels, and antibody production (especially to polysaccharide antigens) undergo significant changes and progressive maturation in the first years of life. It is important to rule out secondary forms of immunodeficiency, such as human immunodeficiency virus infection, protein loss, immunodeficiency secondary to use of immunosuppressive drugs, as well as anatomical and/or functional problems (e.g., asplenia) that may lead to increased susceptibility to infections.

Recognition of PIDDs is essential to start optimal therapies at an early age. These include immunoglobulin substitution for patients with antibody deficiency; allogeneic hematopoietic stem cell transplantation for patients with severe combined immune deficiency; and in some cases, gene therapy or enzyme replacement therapy may be considered. Antimicrobial prophylaxis and aggressive treatment of infections is necessary in most cases of PIDD. Some patients with significant immune dysregulation may benefit from immunosuppressive therapy.

This chapter focuses on defects that primarily affect T and B lymphocytes, the complement system, and innate immunity. The chapter discusses specific immunodeficiency syndromes, reviews etiology and pathogenesis, clinical and laboratory features, treatment, and prognosis. Chaps. 65 and 66 discuss in detail disorders of neutrophil number and function.

Acronyms and Abbreviations

Acronyms and abbreviations used in this chapter include: AD, autosomal dominant; ADA, adenosine deaminase; AD-HIES, autosomal dominant hyperimmunoglobulin E syndrome; AIRE, autoimmune regulator; AK, adenylate kinase; AK2 adenylate kinase 2; ALPS, autoimmune lymphoproliferative syndrome; APECED, autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy; AT, ataxia-telangiectasia; ATLD, ataxia-telangiectasia–like disorder; ATM, ataxia-telangiectasia mutated; BS, Bloom syndrome; BTK, Bruton tyrosine kinase; CD40L, CD40 ligand; CID, combined immune deficiency; CMV, cytomegalovirus; CSR, class switch recombination; CTL, cytotoxic T lymphocyte; CVID, common variable immunodeficiency; D, diversity; FHL, familial hemophagocytic lymphohistiocytosis; G-CSF, granulocyte colony-stimulating-factor; HIES, hyperimmunoglobulin E syndrome; HSE, herpes simplex virus encephalitis; IL, interleukin; IL-7R, IL-7 receptor; IPEX, immune dysregulation, polyendocrinopathy, enteropathy, X-linked; IRAK, IL-1 receptor-associated kinase; J, joining; JAK3, Janus-associated tyrosine kinase 3; LIG4, DNA ligase IV; NBS, Nijmegen breakage syndrome; NEMO, nuclear factor-B essential modulator; NK, natural killer; PNP, purine nucleoside phosphorylase; RMRP, ribonuclease mitochondrial RNA processing; SAP, signaling lymphocyte activation molecule-associated protein; SCID, severe combined immune deficiency; SHM, somatic hypermutation; TLR, toll-like receptor; UNG, uracil N-glycosylase; V, variable; WAS, Wiskott-Aldrich syndrome; WASP, Wiskott-Aldrich syndrome protein; WHIM, warts, hypogammaglobulinemia, infections, myelokathexis; XHIGM, X-linked hyperimmunoglobulin M; XLA, X-linked agammaglobulinemia; XLP1 and XLP2, X-linked lymphoproliferative syndrome types 1 and 2; XLT, X-linked thrombocytopenia; ZAP-70, zeta-associated protein of 70 kDa.

Predominant Antibody Deficiencies

X-Linked and Autosomal Recessive Agammaglobulinemia

Definition and Genetic Features

X-linked agammaglobulinemia (XLA) is the prototypic antibody deficiency characterized by profound hypogammaglobulinemia caused by a maturation defect in B-cell development.1,2 XLA, described in 1953, is one of the first primary immunodeficiencies in which the underlying defect, a mutation of the Bruton tyrosine kinase (BTK) was identified. Autosomal recessive agammaglobulinemia, a variant form of agammaglobulinemia, has been reported in patients with a clinical phenotype resembling XLA including very low B-cell numbers and severe bacterial infections but normal BTK.2 Several responsible gene mutations have been identified, including those involving the B-cell receptor complex heavy chain (IGHM), the surrogate light chain component 5 (IGLL1), the signal transducer complex of the pre-B cell receptors immunoglobulin (Ig) (CD79a), Ig (CD79b), and mutations in the B-cell adaptor molecule BLINK