Phagocytes

Phagocytes are responsible for detecting and migrating to the site of intruder by recognition of microbial products, antibody-mediated detection, or complement. In turn, these cells produce cytokines and signal the adaptive immune system to fight an infection or react to the danger signal. Abnormalities lead to severe and unusual infections. Representative disorders include congenital neutropenia, chronic granulomatous disease, and hyper immunoglobulin E (IgE) syndrome. Four specific genetic defects in phagocyte NADPH oxidase have been described in chronic granulomatous disease. A neutrophil defect should be considered in children who have recurrent abscesses, Staphylococcus infections, granulomas, and an unusual sensitivity to Aspergillus or atypical mycobacterium.

Natural Killer Cells

NK cells confer immunity against viruses, intracellular bacteria, and parasites and provide cytotoxicity against tumor cells. The three disorders that affect NK cells and related interferon gamma (INF-γ)/interleukin-12 (IL-12) pathway are NK cell deficiency (e.g., CD16 deficiency), IFN-γ receptor 1 and 2 defects, and Griscelli syndrome (albinism with immunodeficiency). Patients with defects in the IFN-γ/IL-12 pathway typically present with atypical mycobacterium infection. Patients with isolated NK cell defects are susceptible to herpes viral infections.

Complement

The complement system shares responsibility in host defense, induction of the adaptive immune system, inflammation, and clearance of apoptotic cells and immune complexes. The clinical manifestations of deficiencies early in the complement cascade are susceptibility to infections with Streptococcus pneumoniae and Haemophilus influenzae and rheumatologic abnormalities, such as systemic lupus erythematosus (see Chapter 29). Neisseria infections are more common with defects in later components of the complement cascade. Hereditary angioedema results from a defect in C1 esterase inhibitor enzyme function.

Toll-like Receptors

TLRs are a recently discovered component of the innate immune system. They are a family of pattern recognition receptors whose sole job is immunologic surveillance. TLRs recognize microbial products and danger signals and activate pathways that produce cytokines to recruit the appropriate immune response. Most defects in the TLRs or signaling molecules downstream affect children early in life until the adaptive immune system can mature and contribute to immune regulation. IRAK-4 (interleukin-1 receptor-associated kinase 4) deficiency is an example of a specific defect of the TLR pathway.

Humoral Immune System

The humoral immune system defects, including B cell and antibody defects, make up the most common PIDs. These defects include selective IgA deficiency, transient hypogammaglobulinemia of infancy, X-linked agammaglobulinemia (XLA, or Bruton agammaglobulinemia), hyper IgM syndrome (CD40 ligand deficiency), IgG subclass deficiency, selective antibody deficiency, and common variable immune deficiency (CVID). Patients with humoral defects are typically older than 6 months; they may be diagnosed in the toddler or school-age group. Although CVID can be diagnosed at an earlier age, it is typically diagnosed in adolescents and adults. Children with transient hypogammaglobulinemia of infancy have low quantitative IgG levels with normal IgG function, as noted by protective titers to immunization. Over time, the quantity of IgG normalizes. Children with other humoral defects are unable to respond normally to bacterial infections. Specific defects have been described for some disorders. In XLA, the absence of the Btk gene leads to impairment in B cell development, maturation, function, and receptor signaling. Diagnosis is made by absence of mature B cells. Patients with hyper IgM most commonly have a defect in CD40 ligand (on T cells). Without CD40 ligand binding to CD40 on B cells, the normal switch from IgM to IgG or IgA does not occur. In CVID, patients may have normal mature B cells. However, they have defects in differentiation to immunoglobulin-secreting plasma cells. Characteristic infections seen in humoral defects include severe enteroviral infections in patients with XLA, Pneumocystis carinii pneumonia or Cryptosporidium parvum (associated with sclerosing cholangitis) in patients with hyper IgM, and Giardia infections in patients with XLA or CVID. In addition to infection, some of these patients are more at risk for autoimmune disease and malignancy.

Cell-Mediated Immune System

Defects in the cell-mediated immune system are often quite severe. T cell disorders often begin in early infancy and childhood. These defects affect T cell development or function with varying degrees of defects in the other lymphocytes (i.e., B cells and NK cells). Severe combined immunodeficiency (SCID) is the most serious immune defect and is considered a “medical emergency.” These patients present in infancy with severe viral infections, opportunistic infections, bronchiolitis, and failure to thrive. They typically have absolute lymphocyte counts of less than 2800 cell/microliter and nonfunctioning lymphocytes. Without a bone marrow transplant, these children generally die by 2 years of age. Prompt diagnosis and treatment with transplant increases the survival rate to upward of 90%. One must also consider complete DiGeorge syndrome or secondary immune defects (e.g., HIV) in these very ill infants. Patients with SCID may have a single gene defect or may be a part of an immunodeficiency syndrome such as 22q11.2 deletion syndrome, cartilage hair hypoplasia, or CHARGE (coloboma of the eye, heart defects, atresia of the nasal choanae, retardation of growth or development, genital or urinary abnormalities, and ear abnormalities and deafness) syndrome.

Other T cell immunodeficiencies include chronic mucocutaneous candidiasis, CD4 lymphopenia, and OKT4 epitope deficiency. People with Wiskott-Aldrich syndrome (WAS) present with eczema, thrombocytopenia (small platelets), and T cell defects. Children with ataxia telangiectasia also have T cell defects presenting with ataxia and recurrent infections. These children are also at increased risk for lymphoma.