HI27 - Immunodeficiencies & Immune-Modifying Drugs

Define immunodeficiency.

Partial or total loss of function of one or more components of the immune system leading to increased risk of infection.

What is a primary immunodeficiency?

A congenital or inherited defect in genes for components of the immune system; also known as inborn errors of immunity.

What is a secondary immunodeficiency?

An acquired immunodeficiency caused by environmental factors, diseases, medications, malnutrition, pregnancy, age, stress, trauma, or medical interventions.

What are opportunistic infections?

Infections caused by microorganisms that are normally harmless, often arising from resident microbiota such as fungal or Candida infections; they are difficult to treat.

Why are immunodeficient patients more susceptible to opportunistic infections?

Because immune system defects reduce the ability to control normally harmless organisms.

Why are some primary immunodeficiencies more common in males?

Because many are X-linked recessive disorders; males have only one X chromosome so one defective copy causes disease.

Which lymphocyte deficiency causes the most severe immunodeficiencies?

CD4+ T Cell deficiency.

Approximately how many primary immunodeficiencies exist?

Close to 500 inherited disorders.

What is the approximate incidence of primary immunodeficiencies?

Affects about 1/200 to 1/1000 people.

What are the common presentations of primary immunodeficiencies?

Severe or unusual infections, autoimmune/autoinflammatory diseases, and malignancies.

Why may primary immunodeficiencies be missed at birth?

Maternal antibodies can mask symptoms early in life.

What test is commonly done for newborns to detect severe immunodeficiencies?

Blood panel including tests for T-cell receptor gene rearrangement failure.

What do pyogenic infections indicate about immune defects?

Possible antibody, complement, or phagocyte deficiency.

What do persistent fungal or viral infections suggest?

Defects in T cell function.

What two innate immune components are typically affected in innate immune deficiencies?

Complement function and phagocytosis.

What are the two major consequences of complement deficiencies?

Reduced opsonization/phagocytosis of extracellular bacteria and loss of membrane attack complex formation.

Which autoimmune disorder resembles symptoms of classical complement pathway deficiency?

Systemic Lupus Erythematosus (SLE).

Why do late complement deficiencies increase susceptibility to Neisseria meningitidis?

Because MAC formation is required for defense against Neisseria species.

How much does meningitis risk increase in late complement deficiency?

10,000-fold increase (from 1:2,000,000 to 1:200).

What ocular condition may occur secondary to meningococcemia?

Ischemic optic neuropathy or retinal vascular occlusions.

What is Paroxysmal Nocturnal Hemoglobinuria caused by?

Deficiency of complement regulators DAF (CD55) and Protectin (CD59).

What are signs of PNH?

Morning hemoglobinuria (blood in urine), anemia, dysphagia/odynophagia, high risk of fatal thrombosis.

What causes hereditary angioedema?

Deficiency of C1 inhibitor.

What are symptoms of hereditary angioedema?

Sudden swelling of the face, GI tract, or airway.

"What is the treatment for hereditary angioedema?"

"Exogenous C1 inhibitor supplementation."

"What causes Leukocyte Adhesion Deficiency?"

"Defects in integrins or complement receptors, preventing neutrophils and monocytes from exiting blood vessels or phagocytosing complement-opsonized bacteria."

"What are ocular manifestations of Leukocyte Adhesion Deficiency?"

"Recurrent severe conjunctivitis and keratitis with poor healing and scarring."

"What causes Chronic Granulomatous Disease?"

"Phagocytes cannot produce superoxide (O2-), preventing killing of ingested bacteria."

"What are ocular manifestations of CGD?"

"Granulomatous uveitis, chorioretinal lesions, conjunctivitis, keratitis, and eyelid abscesses."

"What causes Chediak-Higashi Syndrome?"

"Defect in vesicle fusion, preventing phagosomes from fusing with lysosomes."

"What infections occur in Chediak-Higashi Syndrome?"

"Persistent and recurrent bacterial infections."

"What bacteria pose major threats in antibody deficiencies?"

Encapsulated pyogenic bacteria: Haemophilus influenzae, Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus.

"Why are these bacteria dangerous to antibody-deficient patients?"

"They are not recognized well by innate phagocyte receptors and rely on antibody/complement for clearance."

"What causes X-linked Agammaglobulinemia?"

"BTK deficiency preventing pre-BCR checkpoint activation; heavy chains rearranged but cannot signal."

"When does X-linked Agammaglobulinemia appear?"

"Around 6 months of age, when maternal antibodies wane."

"What is the outcome of X-linked Agammaglobulinemia?"

"Frequent bacterial infections and chronic lung disease from bronchiectasis."

"What ocular infections occur in X-linked Agammaglobulinemia?"

"Recurrent bacterial conjunctivitis, blepharitis, and keratitis."

"What is the treatment for X-linked Agammaglobulinemia?"

"Antibiotic prophylaxis and monthly IVIG (gamma globulin)."

"What characterizes Common Variable Immune Deficiency?"

"Low IgM, IgG, and IgA; recurrent respiratory and sinus infections; often diagnosed in 30s-40s."

"What ocular findings occur in CVID?"

"Recurrent bacterial conjunctivitis and keratitis; dry eye from chronic ocular surface inflammation."

"What causes Hyper-IgM Syndrome?"

"Defects in CD40, CD40L, or downstream signaling → loss of T-cell help."

"What immunological consequences occur in Hyper-IgM Syndrome?"

"No germinal centers, absent class switching, impaired macrophage activation; IgM high but IgG/A/E low."

"What infections are Hyper-IgM patients susceptible to?"

"Pyogenic and encapsulated bacteria."

"What is the most common primary immunodeficiency?"

"Selective IgA deficiency."

"What infections occur in IgA deficiency?"

"GI and respiratory infections, and recurrent conjunctivitis, blepharitis, and keratitis."

"What are examples of rare B cell deficiencies?"

"Selective IgG deficiency and selective IgM deficiency."

"What is the major risk of T cell deficiencies?"

"Severe Combined Immunodeficiency (SCID) and vulnerability to viral, fungal, and opportunistic infections."

"What ocular findings occur in T cell deficiencies?"

"Severe viral/fungal keratitis, chronic conjunctivitis, CMV/HSV/VZV retinitis, chronic mucocutaneous candidiasis."

"Why are CD4+ T cell deficiencies severe?"

"CD4+ T cells coordinate all adaptive responses including B cell help, innate immune activation, and CD8+ activation; deficiency is uniformly fatal without transplant."

"What causes MHC Class I deficiency?"

"Failure to transport peptides into ER → impaired CD8+ T cell development."

"What infections occur in MHC Class I deficiency?"

"Increased viral infections, especially respiratory."

"What infections occur in NK cell deficiency?"

"Herpesvirus infections (HSV, VZV, EBV)."

"What causes secondary B cell deficiencies?"

"Malnutrition leading to decreased IgG synthesis."

"What diseases cause secondary T cell deficiencies?"

"AIDS, measles, immunosuppressive drugs, chemotherapy."

"What causes secondary complement deficiency?"

"Liver failure or dysfunction (cirrhosis, hepatitis B/C, malnutrition)."

"What is neutropenia and what causes it?"

"Neutrophils <500/μL, often due to chemotherapy or AIDS; predisposes to pyogenic bacteria."

"What is asplenia?"

"Absence or dysfunction of spleen, leading to susceptibility to encapsulated bacteria."

"What conditions cause functional asplenia?"

"Sickle cell disease, cirrhosis, celiac disease, SLE, IBD, bone marrow transplant."

"What are immunomodulatory drugs?"

"Drugs that suppress or stimulate immune function, including NSAIDs, corticosteroids, cytotoxic drugs, T-cell inhibitors, biologics, and some antibiotics."

"What do ibuprofen and naproxen do?"

Reversibly inhibit COX-1/COX-2, reducing PGE2 synthesis; analgesic, antipyretic, and anti-inflammatory at high doses.

"What risks are associated with NSAIDs?"

"GI ulcers, kidney impairment, cardiovascular risk, harmful in 3rd trimester of pregnancy, and contraindicated in IBD."

"What is aspirin's mechanism?"

"Irreversibly inhibits COX-1 and modifies COX-2; reduces prostaglandin production and induces lipoxin synthesis."

"What is a major aspirin risk in children?"

Reye's syndrome (brain and liver damage); therefore contraindicated in children/teens.

"Why is acetaminophen not an NSAID?"

"Because it does not suppress inflammation; only inhibits COX in the CNS."

"What is the mechanism of corticosteroids?"

"Diffuse into cells, bind steroid receptors, inhibit NF-κB activation, suppress cytokines, prostaglandins, leukotrienes, and leukocyte extravasation."

"What are corticosteroids intended to do?"

"Reduce inflammation and suppress innate immune activation."

"What infections are corticosteroid users vulnerable to?"

"Bacterial, viral (HSV, VZV), and fungal ocular infections."

"What systemic side effects do corticosteroids cause?"

"Weight gain, fluid retention, diabetes, mood swings, osteoporosis, and immunosuppression."

"What are topical corticosteroid risks?"

"Skin atrophy and increased risk of fungal or bacterial infection."

"What are inhaled steroid uses?"

"Asthma, allergic rhinitis, severe aphthous ulcer treatment."

"What are systemic steroid uses?"

"SLE, RA, IBD, organ transplant rejection prevention."

"What do cytotoxic drugs target?"

"Dividing cells; prevent replication of activated T cells or autoimmune cells."

"What are major cytotoxic drug side effects?"

"Leukopenia, mucositis, gastrointestinal toxicity, infections."

"What does methotrexate do?"

"Inhibits thymidine synthesis; used in cancer, GVHD, RA, psoriasis, SLE, Crohn's."

"What drugs inhibit nucleotide synthesis?"

"Azathioprine and mycophenolic acid."

What are the uses of drugs that reduce nucleotide synthesis?

"Graft rejection prevention, RA, Crohn's disease, lupus nephritis."

"What is cyclophosphamide used for?"

"Chemotherapy, anti-rejection, severe SLE/RA, MS."

"What blocks NFAT signaling?"

"Cyclosporine A and tacrolimus; prevent IL-2 production and T cell proliferation."

"What are cyclosporine/tacrolimus side effects?"

"Infections, nephrotoxicity, gingival hyperplasia (CsA), impaired bone healing, herpesvirus reactivation."

"What drug blocks IL-2 signaling via mTOR inhibition?"

"Rapamycin (Sirolimus)."

"What are rapamycin side effects?"

"Impaired wound healing, diabetes-like syndrome, thrombocytopenia."

"Which antibiotics are immunomodulatory?"

"Tetracyclines (sub-antimicrobial dose)."

"What are tetracycline immunomodulatory effects?"

"Inhibit cytokines, prostaglandins, and MMPs; used in acne."

"What are tetracycline side effects?"

"Tooth staining, impaired fetal bone development, photosensitivity."

"What are biologics?"

"Pharmaceuticals produced from living organisms (cells, bacteria, animals); include monoclonal antibodies and cytokine inhibitors."

"What risks are associated with animal-derived antibodies?"

"Serum sickness and loss of efficacy."

"What percentage of 2024 pharmaceutical spending was biologics?"

"37% (about $511 billion)."

"What is the typical patient cost for biologics?"

"$1,000-$3,000+ per month."

"What do antithymocyte globulins do?"

"Polyclonal antibodies that deplete developing T cells; used to prevent transplant rejection."

"What does rituximab target?"

"CD20 on B cells; used for RA, autoimmune skin disease, Sjögren syndrome, vasculitis."

"What do anticytokine biologics do?"

"Block inflammatory cytokines such as IL-1, IL-4/13, IL-6, IL-17A, IL-12/23, and TNF-α."

"What determines immunogenicity of monoclonal antibodies?"

"Degree of humanization: Mouse > Chimeric > Humanized > Fully Human (least immunogenic)."