Systemic Infections, Autoimmunity, Toxicology, and Cancer Principles

Systemic Disease Reasoning Map

Systemic infection becomes multisystem disease when a microbe reaches blood or lymph, survives host defenses, targets endothelium or macrophages, or triggers an immune response that injures distant organs. Step 1 questions often ask why a pathogen disseminates. Encapsulated bacteria resist opsonization when complement or splenic macrophage function is impaired, so asplenic patients are vulnerable to overwhelming sepsis from organisms such as Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae.

Intracellular organisms survive inside macrophages and require Th1 immunity, IL-12 from macrophages, interferon-gamma from Th1 cells and NK cells, and TNF-alpha for granuloma maintenance. Disseminated tuberculosis, histoplasmosis, coccidioidomycosis, and nontyphoidal salmonella are more likely when cell-mediated immunity is weak. Rickettsia rickettsii infects endothelial cells, producing vasculitis, capillary leak, edema, thrombocytopenia, and rash that involves wrists, ankles, palms, and soles.

Neisseria meningitidis can produce petechiae, purpura fulminans, DIC, and adrenal hemorrhage through endotoxin-driven cytokine release. Staphylococcus aureus and Streptococcus pyogenes toxic shock syndromes are superantigen diseases: toxins cross-link MHC class II on antigen-presenting cells with T-cell receptors outside the peptide groove, activating many T cells and causing massive IL-2, IFN-gamma, TNF-alpha, fever, rash, hypotension, and multiorgan injury. Epstein-Barr virus infects B cells through CD21, but the atypical lymphocytosis of mononucleosis reflects reactive CD8 T cells.

Cytomegalovirus causes mononucleosis-like illness with less pharyngitis and heterophile-negative testing, and severe tissue-invasive disease in immunocompromised patients. HHV-8 drives Kaposi sarcoma through infected endothelial-lineage cells and angiogenic cytokines. Schistosoma eggs trigger granulomatous inflammation and fibrosis; portal hypertension or bladder squamous cell carcinoma depends on species and tissue deposition. Leishmania donovani survives in macrophages and causes visceral disease with fever, hepatosplenomegaly, and pancytopenia.

Chagas disease begins with bloodstream trypomastigotes and later causes chronic myocarditis, dilated cardiomyopathy, megaesophagus, and megacolon through parasite persistence and immune-mediated injury to muscle and enteric neurons. Hypersensitivity mechanisms organize many systemic diseases. Type I hypersensitivity is IgE-mediated mast cell activation after prior Th2 sensitization. IL-4 and IL-13 promote class switching to IgE, IgE binds Fc-epsilon-RI on mast cells, and re-exposure cross-links IgE to release histamine, tryptase, leukotrienes, prostaglandins, and cytokines.

Anaphylaxis is distributive shock from vasodilation, permeability, and bronchoconstriction. Type II hypersensitivity is antibody-mediated injury against cell surface or matrix antigens. It can cause complement-mediated lysis, opsonization, receptor blockade, or receptor stimulation, as in autoimmune hemolytic anemia, Goodpasture disease, myasthenia gravis, and Graves disease. Type III hypersensitivity is soluble immune complex deposition. Complexes activate complement, especially C3a and C5a, recruit neutrophils, and produce granular immunofluorescence with low serum complement when consumption is significant.

Examples include serum sickness, poststreptococcal glomerulonephritis, systemic lupus erythematosus nephritis, IgA vasculitis, mixed cryoglobulinemia, and some drug reactions. Type IV hypersensitivity is T-cell mediated: Th1 macrophage activation causes granulomas and contact dermatitis, Th17 recruits neutrophils, and CD8 T cells directly kill target cells. Autoimmune and vasculitic diseases should be classified by target. Small-vessel immune complex vasculitis often presents with palpable purpura, renal disease, and complement abnormalities.

IgA vasculitis causes IgA immune complex deposition after an upper respiratory infection with abdominal pain, arthralgia, palpable purpura, and nephritis. Goodpasture disease is type II anti-basement membrane antibody against type IV collagen in lung and kidney, causing linear immunofluorescence, hemoptysis, and rapidly progressive glomerulonephritis. Granulomatosis with polyangiitis is a pauci-immune necrotizing granulomatous vasculitis of upper airway, lung, and kidney associated with PR3-ANCA. Eosinophilic granulomatosis with polyangiitis has asthma, eosinophilia, neuropathy, and MPO-ANCA in many cases.

Polyarteritis nodosa affects medium arteries, spares pulmonary arteries, can be linked to hepatitis B immune complexes, and causes renal, GI, skin, and neurologic ischemia. Temporal arteritis is granulomatous large-vessel vasculitis with headache, jaw claudication, vision risk, and association with polymyalgia rheumatica. Kawasaki disease is medium-vessel vasculitis in children with coronary aneurysm risk driven by intense cytokine-mediated vascular inflammation. Toxicology patterns are physiologic experiments.

Opioids cause coma, respiratory depression, and miosis through mu receptor activation that decreases brainstem respiratory drive and GI motility. Organophosphates irreversibly inhibit acetylcholinesterase, producing muscarinic excess, nicotinic weakness, and CNS toxicity. Anticholinergic toxicity blocks muscarinic receptors, causing hyperthermia, dry skin, mydriasis, urinary retention, ileus, delirium, and tachycardia. Sympathomimetic toxicity increases catecholamine signaling with hypertension, tachycardia, diaphoresis, mydriasis, agitation, hyperthermia, and ischemia.

Carbon monoxide binds hemoglobin with high affinity and shifts the oxyhemoglobin dissociation curve left, so PaO2 can be normal while tissue oxygen delivery is impaired; it also impairs mitochondrial respiration. Cyanide inhibits cytochrome c oxidase, blocking oxidative phosphorylation and causing severe lactic acidosis with high venous oxygen content. Acetaminophen overdose saturates glucuronidation and sulfation, increasing CYP-mediated NAPQI formation; depleted glutathione permits centrilobular hepatic necrosis.

Salicylates stimulate the medullary respiratory center causing respiratory alkalosis, then uncouple oxidative phosphorylation and produce an anion gap metabolic acidosis. Cancer biology ties molecular damage to systemic signs. Activating oncogenes are gain-of-function drivers: RAS locks proliferative signaling on when GTPase activity is impaired; MYC increases transcription for growth and metabolism; BCR-ABL is a constitutively active tyrosine kinase; HER2 amplifies growth signaling.

Tumor suppressors are loss-of-function barriers: RB restrains the G1-to-S checkpoint through E2F binding; p53 senses DNA damage and induces cell-cycle arrest, repair, senescence, or apoptosis; APC promotes beta-catenin degradation; PTEN opposes PI3K-AKT growth signaling; BRCA1 and BRCA2 support homologous recombination repair. DNA repair defects create mutator phenotypes, such as mismatch repair loss with microsatellite instability in Lynch syndrome or nucleotide excision repair failure in xeroderma pigmentosum.

Malignant cells invade by losing adhesion, often through reduced E-cadherin, attaching to laminin, degrading type IV collagen with matrix metalloproteinases, migrating through stroma, entering vessels, surviving shear stress and immunity, and colonizing permissive organs. Carcinomas often spread first by lymphatics; sarcomas more often spread hematogenously. Portal drainage carries colorectal cancer to liver, while systemic venous drainage can carry tumors to lung; ovarian and gastric tumors may seed peritoneal surfaces. Angiogenesis requires hypoxia-inducible factor and VEGF.

Paraneoplastic syndromes are remote effects not explained by local mass or metastasis: PTHrP from squamous cell carcinoma causes hypercalcemia; ectopic ACTH from small cell lung carcinoma causes Cushing syndrome; ADH secretion causes hyponatremia; antibodies against presynaptic calcium channels cause Lambert-Eaton syndrome; mucin-producing adenocarcinomas can cause migratory thrombophlebitis. Cachexia reflects TNF-alpha, IL-1, IL-6, proteolysis-inducing factors, anorexia, insulin resistance, and muscle wasting, not simply poor intake.