Immunodeficiency Diseases
An immunodeficiency condition results from one or more abnormalities of the immune system that manifest as an inability to fight off or recover from an infection.
Functions of the Immune System
Defense
Antimicrobial activity. If it’s working too effectively, we develop hypersensitivities aka allergies. When it’s not effective, we get immune deficiencies.
Homeostasis
Removal of damaged and aging cells. If the body is too good at targeting its own cells, we get autoimmune disease.
Surveillance
Removal of mutant cells. If this surveillance system malfunctions, we get cancer.
Types of Immunodeficiencies
Primary
Present at or around birth. Caused by defects in genes that control the expression of immune responses. Generally more rare than secondary immunodeficiencies.
Secondary
Acquired as a result of some other issue, including infectious diseases, trauma, and exposure to certain drugs or noxious compounds such as radiation. Also can be acquired with age.
Primary Immunodeficiencies
Phagocytic cell deficiencies
In quantitative defects, levels of phagocytic cells are reduced, can be congenital or acquired. This increases susceptibility to infection. Qualitative defects are cases where phagocyte counts are fine but the cells are defective. This can cause to abnormal response to infection
Examples of quantitative deficits
- Neutropenias: Reduced numbers of polymorphonuclear leukocytes (PMNs) resulting from a genetic defect or an acquired deficiency.
- Hyposplenism: Reduced number of macrophages because of surgical splenectomy or hemolytic anemia (sickle cell).
Leukocyte adhesion deficiencies (LAD)
Deficiency in adhesion molecules prevents macrophages from addressing infections.
In LAD1 I, we see ulcerative lesions that have minimal inflammation and a lack of pus. Ulcers just get really scabbed over. In young children with LAD I, you will see delayed umbilical cord separation and periodontitis.
In LAD II, there is a deficiency in adhesins, preventing cells from leaving the vessels.
Defects of granule formation and content
Chediak-Higashi syndrome is characterized by the fusion of multiple primary granules into giant granules and impaired lysosomal trafficking. T cell and B cell mediated immunity are functional but NK cells have lost their cytotoxicity. Patients present with partial albinism and recurrent bacterial infections.
Defects of oxidative metabolism
A defect in the NADPH oxidase complex, meaning the macrophage can’t complete destruction of pathogens.
Chronic granulomatous disease (CGD) is characterized by chronic infection with catalase positive bacteria. The most common etiology of CGD is an X-linked genetic mutation of NADPH oxidase; it can also be inherited in an autosomal recessive fashion. Granulomas have an area of central necrosis just like those seen in TB, meaning they are caseating granulomas.
IFN-gamma and IL-12 pathway defects
IL-12 is used to activate NK cells and TH1 cells to produce IFN-gamma and IL-2. IFN-gamma will trigger macrophages to further upregulate the inflammatory response. The issue arises with an autosomal recessive mutation in the IFN-gamma receptor.
Complement deficiencies
Deficiencies in complement leave the body vulnerable to mostly bacterial, some viral infections.
Early complement component deficiencies like C3b increases susceptibility to staph infections.
Late component deficiency (e.g. C5-C9) will increase susceptibility to Neisseria infections, as the MAC complex is what neutralizes those pathogens.
Ab (B cell) deficiencies
When B cells have dysfunctional or deficient enzymes in their signal transduction pathways.
Cell-mediated (T cell) deficiencies
DiGeorge Syndrome is the failure of the thymus to grow because of embryonic aortic arch defects, causing a congenital T cell defect. Patients are especially susceptible to viral and fungal infections. Presents with distinct facial features and cardiac defects.
Combined B and T cell deficiencies
Severe Combined Immunodeficiency (SCID): Underlying defects are caused by failure of lymphocyte proliferation
This can stem from various causes
- A deficiency of proteins that make up receptors or associated signal transduction pathways
- Toxicity from chemical buildup in B and T lymphocytes
- Defects in the DNA repair pathways in B and T cells.
Bubble Boy: Male patient born with X-linked SCID. A blood test found that he had a deficiency in the gamma chain protein that makes up many IL receptors. He died of B-cell lymphoma after a bone marrow transplant.
Diagnosis of Immunodeficiency
Signs and symptoms
- Several ear, sinus, or deep-seated infections within a year
- Several pneumonias within a year
- No response to antibiotics or requirement for IV antibiotics
- Failure of infant to gain weight
- Persistent thrush in mouth/skin after 1 year
- Recurrent deep skin/organ abscesses
Diagnosis
TREC tests in newborns are assays which reveal T cell receptor excision circles. These result from the modification of B and T cells for enhancing receptor diversity. No circle, poor diversity.
Treatment
- Control of infections with antibiotics
- Administer IV, IM, or subcutaneous immunoglobulins
- Gene therapy with retroviral vectors has been used in the past, but isn't ready for primetime