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Primary Immunodeficiencies

Immunodeficientia primaria

For medical students2 min readUpdated 2026-10-10

Primary immunodeficiencies (PIDs) are genetically determined disorders affecting specific or nonspecific immunity. The primary clinical presentation is an increased susceptibility to recurrent infections, typically debuting between 6 months and 2 years of age.

Age of Onset6 months to 2 years — the window of initial clinical presentation.

EtiologyMost forms are genetically determined defects.

Primary SymptomIncreased susceptibility to severe recurrent infections.

Common PathologyIsolated IgA deficiency is highly prevalent in the population.

Classification and Epidemiology

Immune deficiencies are broadly divided into two groups based on origin:

Primary immunodeficiencies: Genetically determined disorders where the immune system itself is intrinsically defective. They are relatively rare (with the exception of IgA deficiency).
Secondary immunodeficiencies: Acquired conditions developing secondary to other diseases. They are widely prevalent. For example, approximately 90% of viral infections are accompanied by transient immunosuppression or altered responses to heterologous antigens.

Based on the affected component, defects are classified as specific (selective impairment of B cells, T cells, or combined B/T cell defects) and nonspecific (dysfunction of the complement system, phagocytes, or natural killer cells).

Humoral Immunity (B-Cell) Defects

Bruton X-linked Agammaglobulinemia. An X-linked disorder affecting males. Serum immunoglobulins are virtually absent (trace amounts of IgG may be present), along with a complete absence of B lymphocytes and plasma cells. T cells remain normal. Morphologically, lymph nodes and the spleen lack germinal centers, and the palatine tonsils are rudimentary. Patients suffer from pyogenic bacteria (e.g., staphylococci) causing recurrent otitis media, bronchitis, pneumonia, and skin infections. Autoimmune conditions resembling rheumatoid arthritis develop in 50% of children, along with systemic lupus erythematosus (SLE) and dermatomyositis.
Common Variable Immunodeficiency (CVID). A heterogeneous group of disorders with variable inheritance (congenital, acquired, sporadic, or familial). It is characterized by hypogammaglobulinemia (reduced levels of all antibody classes or IgG alone). Unlike Bruton disease, morphology reveals hyperplasia of B-cell zones (lymphoid follicles). Clinical features include bacterial and severe enteroviral infections, recurrent herpes, and persistent diarrhea (caused by Giardia lamblia). In 20% of cases, rheumatoid arthritis, pernicious anemia, or hemolytic anemia co-occur.
Isolated IgA Deficiency. A very common form associated with impaired B-lymphocyte differentiation. It can be familial or acquired (following measles or toxoplasmosis). A lack of secretory IgA impairs mucosal defense, leading to sino-pulmonary infections, a high incidence of respiratory allergies, and autoimmune diseases (SLE, rheumatoid arthritis).

T-Cell and Combined Immunodeficiencies

DiGeorge Syndrome. A form of selective T-lymphocyte deficiency. Notably, it is not genetically inherited: it results from an in utero developmental insult around the 8th week of gestation. It manifests as thymic hypoplasia (complete loss of cell-mediated immunity), absence of parathyroid glands (leading to tetany), and congenital heart and great vessel defects.
Severe Combined Immunodeficiencies (SCID). Combined defects of T and B lymphocytes with autosomal recessive or X-linked inheritance. Morphology depends on the specific mutation: in adenosine deaminase (ADA) deficiency, the thymus is hypoplastic and devoid of lymphoid cells; in other forms, generalized lymphoid hypoplasia is seen. Without hematopoietic stem cell transplantation, it is fatal within the first few years of life.
Wiskott-Aldrich Syndrome. An X-linked recessive disorder characterized by the classic triad: immunodeficiency, thrombocytopenia, and eczema. The thymus is morphologically normal. It is marked by a high susceptibility to infections and early mortality.

Genetic Deficiencies of the Complement System

Mutations can affect any complement component or inhibitor, impairing innate immune defenses.

C3 Deficiency. A critical condition because the C3 component is essential for both the classical and alternative pathways of complement activation. It leads to heightened susceptibility to pyogenic bacteria.
Hereditary Angioedema. Characterized by localized edema of the skin and mucosal membranes.

Mnemonic

To remember the features of Wiskott-Aldrich syndrome, use the triad TIE: Thrombocytopenia, Infections (immunodeficiency), Eczema. Note that the thymus remains morphologically normal in this condition.

Frequently asked questions

What genetic mutations cause severe combined immunodeficiencies (SCID)?

Severe combined immunodeficiencies (SCID) are caused by various genetic mutations that impair lymphocyte development. Key genetic defects include:

V(D)J recombination defects — including mutations in the RAG-1 and RAG-2 genes, as well as mutations in the gene encoding DNA-dependent protein kinase.
Enzyme deficiencies — absence of adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP).
Receptor apparatus defects — mutations in the common $\gamma_c$ chain of cytokine receptors (X-linked form) and deficiency of the IL-7 receptor $\alpha$ chain.
Jak3 tyrosine kinase deficiency — disrupts intracellular signal transduction from the $\gamma_c$ receptor chain.

What is the pathogenesis of hereditary angioedema?

The pathogenesis of hereditary angioedema involves an inherited defect in the C1 esterase inhibitor ($C1_{\text{inh}}$). Normally, this protein belongs to the serpin family, specifically binding classical pathway components and acting as a kallikrein inhibitor. Its deficiency results in excessive kallikrein activation and subsequent overproduction of kinins. This leads to a life-threatening condition characterized by localized edema of the skin and mucous membranes.

At what age do primary immunodeficiencies typically present?

Clinical onset for most forms occurs between 6 months and 2 years of age. The primary manifestation is an increased susceptibility to recurrent infections.

How does DiGeorge syndrome fundamentally differ from other forms?

It is not a genetically inherited disorder. Rather, it is the result of an in utero developmental insult at the 8th week of gestation, leading to thymic and parathyroid hypoplasia.

How do lymph nodes change in Bruton agammaglobulinemia?

Lymph nodes and the spleen completely lack germinal centers, and the palatine tonsils remain rudimentary.

Why is a deficiency of complement component C3 particularly dangerous?

Component C3 is critical because it is required to initiate both the classical and alternative pathways of complement activation.

Go deeper

Mechanisms of autoimmune complications (SLE, rheumatoid arthritis) in the setting of immunodeficiencies.
The role of Giardia lamblia and enteroviruses in the pathogenesis of infections during common variable immunodeficiency.
Morphological variants of thymic architecture in various genetic forms of SCID.
Pathogenesis of sino-pulmonary infections in isolated IgA deficiency.
Causes of tetany and congenital heart defects in DiGeorge syndrome.