Immunodeficiency diseases have traditionally been defined as defects in the development and function of T and B cells, the primary effector cells of specific cellular and humoral immunity respectively. However, it has become increasingly evident that innate immune mechanisms contribute greatly to host defense, either acting alone or by enhancing specific T and B cell responses.
There are also many conditions that present in a manner identical to inherited primary immunodeficiency disorders (PID), but are caused by acquired defects such as somatic mutations.
Normal immune system function
The immune system detects and eliminates non-self antigens, such as bacteria and viruses.
Innate immunity is non-specific, and is mediated by neutrophils and macrophages which respond to local inflammatory and cellular injury signals. These signals consist of antigens present on the pathogen surface, which are conserved among species, as well as the stress-induced molecules which are released by the host as a part of its reaction to inflammation, infection or other types of disease.
These antigens bind to and activate specific receptors, both stimulatory and inhibitory. This interaction enables immune activation during pathogen exposure, but keeps the immune system quiet when there is no danger, and so prevents the development of auto-immune disease.
On the other hand, acquired immunity involves the binding of antigen-specific receptors on the surface of lymphocytes to antigens on the surface of pathogens. The response may be in the form of activation of pathogen-killing lymphocytes, which is called cellular immunity. Another form of specific immunity is the humoral response, in which antibodies are produced by plasma cells generated in response to antigenic stimulation.
Antibody deficiency may be both primary and secondary, depending on the age at which they manifest. Some primary forms may be due to single mutations, and others depend on the activation of hereditary factors by environmental factors.
Primary immunodeficiency may be classified as follows:
Inherited B cell disorders
These leading to severe early infections and often death as a result of markedly reduced lymphoid tissue in the body. Genetic defects in B cell development are responsible for these conditions, and 85% of patients with defective early B cell development have Btk mutations, which causes X-linked agammaglobulinemia or Bruton’s agammaglobulinemia.
Inherited T cell disorders
These usually cause recurrent opportunistic yeast infections.
Inherited combined immunodeficiency
This affects both T and B cells and is often deadly in infancy, without early treatment. Severe combined immunodeficiency (SCID) is an umbrella term for a variety of disorders that present early in life with both humoral and cellular defects in immunity, leading to death within a few years. About 1 in 50,000 to 100,000 babies are born with one of these conditions.
They suffer from infections by bacteria, viruses and fungi, which are both recurrent and persistent, leading to failure to thrive. The X-linked form is responsible for half of all cases, but there are also many cases due to adenosine deaminase deficiency, interleukin-7 receptor alpha chain deficiency and JAK3 deficiency. These patients have a low T cell count, and no NK cells. B cells are normal or high, though impaired in function.
Immunodeficiency may also be an acquired condition, due to infections, malignancies and metabolic disorders which interfere with the normal production or function of immune cells. Some important causes of acquired immunodeficiency include infections with HIV, cytomegalovirus or measles; blood dyscrasias such as aplastic anemia or leukemia; and metabolic conditions such as diabetes mellitus, or renal failure.
Symptoms of immunodeficiency
Immunodeficiency should be suspected if symptoms such as recurrent bacterial infections of the ears, sinuses or lungs; poor response to antibacterial therapy and delayed recovery; or opportunistic infections; are present.
Immunodeficiency may result in:
- Persistent or recurrent sicknesses, especially infections
- Increased risk of certain cancers or tumors
Diagnosis and treatment
A variety of tests may be necessary to diagnose an immunodeficiency disorder. These include:
- Blood complement levels,
- HIV testing
- Immunoglobin levels
- Blood or urine electrophoresis to measure antibody levels and types
- White cell count and neutrophil function assays
- Cytokine assays following stimulation
- Lymphocyte count and proliferation asays
Treatment is aimed at preventing and treating infectious diseases. It involves quarantine from patients with infections or who have received live vaccines. Aggressive and early antimicrobial treatment is necessary in case of infection, which may require the continuation of antibiotics or antifungals on a long-term basis to prevent re-infection.
IgG replacement is essential in all B-cell disorders and many patients with combined disorders. The restoration of immune function is the goal in the T-cell disorders. Thus HLA-matched stem cell transplant is the gold standard for treatment of infants with SCID, with a success rate of 75 to 90%.
Antiviral drugs, interferons, and splenectomy are all options that may be useful in different situations.