Immunosuppression causes and consequences

Study Notes

Immunosuppression can be primary (congenital/inherited) or secondary (acquired).
Primary Immunodeficiencies:
- Include combined immunodeficiencies (affecting both B and T cells), immunoglobulin deficiencies, complement deficiencies, congenital phagocyte defects, and autoinflammatory disorders.
- Also encompass defects in innate immunity and phenocopies (mimicking) primary immunodeficiencies.
Secondary Immunodeficiencies:
- Result from diseases like infections, malnutrition, cancer, diabetes mellitus, and drug-induced immunosuppression.

Agammaglobulinemia:
- 85% are Bruton's disease (X-linked, affecting only males).
- 15% are autosomal recessive.
Hyper IgM syndromes: B cells fail to switch from making IgM to other immunoglobulin types.
Other deficiencies affect various immunoglobulin types, subclasses, and specificities for certain microbes (e.g., Streptococcus pneumonia). Transient hypogammaglobulinemia of infancy is also a type of antibody deficiency.

Severe Combined Immunodeficiency (SCID):
- Primarily affects T, B, and natural killer (NK) cells.
- Often involves mutations in the gamma chain of interleukin (IL) receptors, sometimes affecting downstream signaling molecules.
- Bone marrow transplant is often required.
IL-2: Involved in T cell proliferation.
IL-4: Essential for B cell class switching.
IL-7: Anti-apoptotic, influencing T cell selection.
IL-15: Critical for NK cell development.
DiGeorge Syndrome: A 22q11 deletion syndrome, with varying degrees of T cell immunodeficiency, often leading to underdeveloped parathyroid glands, and potential connective tissue or mental health problems.

1-10% of immunodeficiencies involve the complement system.
Can cause chronic or recurring infections, autoimmune diseases like angioedema, renal disease, vasculitis, and macular degeneration. Can be involved in immune complex diseases, such as Systemic Lupus Erythematosus (SLE).

Normal neutrophils: 2.5-7.5 × 10⁹/L
Moderate neutropenia: 0.5-1 × 10⁹/L
Severe neutropenia: <0.5 × 10⁹/L
Causes: Autoimmune destruction, bone marrow malignancies, aplastic anemia, chemotherapy, vitamin deficiencies (B12, folate, iron), certain medications (phenytoin, chloramphenicol), infections (mononucleosis, hepatitis B and C, HIV, CMV), alcoholism, typhoid fever.
Consequences: When neutrophil count is <1 × 10⁹ /L, the person is immunocompromised, increasing risk of infections. Thrombocytopenia and bleeding may also occur.

EBV (Epstein-Barr virus) can cause hyperkeratosis.
Immunosuppression: Can be caused by diseases or medical interventions (e.g., medications to suppress the immune system after organ transplants or in situations of autoimmunity or allergies). This also encompasses tumors and their microenvironments, which often contain a variety of immune cells that support tumor growth.

Cytotoxic drugs: Used to treat various conditions including cancer, rheumatoid arthritis, and severe Crohn's disease. They inhibit the synthesis of nucleotide bases from folate. Methotrexate is an example.
Corticosteroids such as Prednisone: Inhibit inflammation.
Fingolimod: Inhibits T cell migration, used to treat relapsing multiple sclerosis.
Rapamycin (sirolimus): An antiproliferative agent that targets the mTOR pathway; used to prevent transplant rejection.

Recipient's tissue is damaged by donor T cells reacting to the graft.
Donor T cells encounter recipient's antigens presented on recipient antigen-presenting cells (APCs).
Gut fibroblasts and epithelial cells also express these alloantigens.

Mucositis: Irritation and ulcers affecting oral tissues.
Ulcerations: Sores in the lining of the mouth.
Infection, hemorrhage, xerostomia (dry mouth), and parotitis (inflammation of the salivary glands) are also complications.
Tumours, such as Kapsi's sarcoma, are also possible complications.