• Characterized by rubor (redness), dolor (pain), calor (heat), tumor (swelling), and dunctio laesa (loss of function)
• Inflammtion allows inflammatory cells, plasma proteins (complement) and fluid to exit blood vessels and enter the interstitial space
• Fluid Exudation: Increased vascular permeability, vasodilation, endothelial injury
• Fibrosis: Fibroblast emigration and proliferation; deposition of extracellular matrix  
• Resolution:
• Restoration of normal structure
• Granulation tissue-Highly vascularized, fibrotic
• Abscess- Fibrosis surrounding pus
• Fistula- Abnormal communication
• Scarring- Collagen deposition resulting in altered structure and function

• Neutrophils
• Eosinophils
• Antibody Mediated
• Acute inflammation is rapid in onset (Seconds to minutes)
• Lasts minutes to days
• Characterized by the presence of edema and neutrophils in tissue
• Arise in response to infection (eliminate pathogen) or tissue necrosis ( to clear necrotic debri)
• Immediated response with limited specificity (innate immunity)
• Mediators of Acute Inflammation:
• Toll-like Receptors
• Arachidonic Acid metabolities
• Mast Cells
•  Complement
• Llageman factor (XII)

Toll Like Receptors

TLRs

• Present on cells of the innate immune system
• Macrophages
• Dendritic cells
• Activated by pathogen assocaited molecular patterns (PAMPs) that are commonly shared by microbes
• TLRs on macrophages recognize lipopolysaccharides (PAMP) on the outer membrane of Gm (-) bacteria
• A TLR results in the activation of NF-KB, a nuclear transcription factor that activates immune response genes leading to production of multiple immune mediators
• TLRs are also present on lymphocytes and play an important role in chronic inflammation

• AA is released from the phopholipid cell membrane by phospholipase A and then acted upon by cyclooxygenase or 5-lipoxygenase
• Cyclooxygenase produces prostaglandins
• PGI, PGD, PGE3: mediate vasodilation and increased vascular permeability
• PGEj also mediates pain
• 5-lipoxygenase produced leukotrienes
• LTB attracts and activates neutrophils
• LTC,LTD4, LTE4: mediate vasoconstriction, bronchospasm, and increased vascular permeability. Slow reacting substances of anaphalyxis 

• Wildely distrubited throughout connective tissue
• Activated by:
• Tissue trauma
• Complement proteins C3a C5a
• Cross linking of cell surface IgE by antigen
• Immediate response involved the release of preformed histamine granules which causes
• Vasodilation of arterioles
• Increased vascular permeability
• Delayed response involved the production of AA metabolites particulary Leukotrienes

• Membrane Attack Complex (MAC)- defends against Gm (-) bacteria
• MAC causes bacterial cell lysis and cytotoxicity
• Recruitment of inflammatory cells
• Opsonization of pathogen
• Killing of pathogen
• Classic pathway:  
• Activated by IgM (1) or IgG (2) that is bound to an antigen
• C1q binds either directly to the pathogen or to antibody bound to pathogens and allows autoactivation of C1r
• C1r cleaves C1s
• C1s cleaves C4
• C4 binds to C2 and allows C1s to cleave C2
• C4bC2a is C3 convertase and cleaves C3
• C4bC2aC3b is C5 convertase and cleaves C5
• C5b binds to C6 and C7
• C5bC6C7 complexes bind to the membrane via C7
• C8 binds to this complex and inserts into the cell membrane
• C9 molecules bind to the complex and polymerize.  1-16 molecules of c9 bind to form a pore in the membrane
• Mannose Binding Lectin Pathway
• Binds to mannose on microorganisms
• 2 molecules of both MASP-1 and MASP-2 form the C1 like complex 
• The rest of the pathway is like classical pathway
• Alternative Pathway
• Activated by microbial products
• Hydrolysis of C3 to C3b
• Factor B binds and is cleaved by factor D to C3bBb  which is C3 convertase
• C3bBb cleaves C3 and makes C5 convertase C3bBb3b
• from C5 on this is the same as classical pathway
• C1, C2, C3, C4: Viral neutralization
• C3b: Opsonization
• C3a, C5a: Anaphylaxis
• C5a: Neutrophil chemotaxis
• C5b-C9: Cytolysis by MAC
• C3b and IgG are the two 1° opsonins in bacterial defense
• C3b also helps clear immune complexes
• Decay-accelerating factor (DAF) and C1 esterase inhibitor help prevent complement activation on self cells (RBC)

Hereditary angioedema

ACE inhibitors are contraindicated with deficiency

Severe, recurrent pyogenic sinus and respiratory tract infections

Increased susceptibility to type III hypersensitivity reactions

• Inactive proinflammatory protein produced in the liver
• Activated in response to subendothelial tissue or collagen
• Activates coagulation and fibrinolytic systems
• Complement
• Kinin system

• Kinin cleaves high molecular weight kininogen to bradykinin which mediates vasodilation and increased vascular permeability and well as pain  

• Rubor (Redness) and Calor (warmth)
• Due to vasodilation which results in increased blood flow
• Occurs via relaxation of arteriolar smooth muscle, key mediators are histamine, prostaglandins, and bradykinin
• Tumor (swelling)
• Due to leakage of fluid from postcapillary venules into the interstitial space (exudate)
• Key mediators are:
• Histamine-Causes endothelial cell contraction
• Cell damage-Resulting in endothelial cell distruption
• Dolor (Pain)  
• Bradykinin
• PGE
• Fever
• Pyrogenes (LPS from bacteria) cause macrophages to release IL-1 and TNF which increase cyclooxygenase activity in perivascular cells of the hypothalmus
• Increases PGR raises temp set pt

• Margination
• Vasodilation slows blood flow in postcapillary venus.  RBCs aggregate into rouleaux
• Cells marginate from center of flow to the periphery
• Rolling
• Selectin "speed bumbs" are upregulated on enothelial cells
• P-selectin release from Weibel Patade bodies is mediated by histamine
• E-selectin is induced by TNF-α and IL-1
• Selectins bind sialyl Lewis X on leukocytes
• Interaction results in rolling of leukocytes along vessel wall
• Adhesion
• Cellular adhesion molecules (ICAM, VCAM) are upregulated on endothelium by TNF-α and IL-1
• Integrins are upregulated on  leukocytes by C5a and Leukotriene B4 (LTB4)
• Interactiosn between CAMs and integrins results in firm adhesion of leukocytes to the vessel wall
• Transmigration and Chemotaxis
• Leukocytes transmigrate across the endothelium of postcapillary venules
• Neutrophils dissolve the basement membrane
• Exudate accumulates in interstitial tissue
• Neutrophils are attracted by bacterial products IL-8, C5a, LTB4
• Binding of these products to the neutrophil causes Ca²⁺ release, which increases neutrophil motility
• Phagocytosis
• Consumption of pathogens or necrotic tissue
• Phagocytosis is enhanced by opsonins IgG and C3b
• Pseudopods extend from leukocytes to form phagosomes which are internalized and merge with lysosomes to produce phagolysosomes
• Destruction of phagocytosed material
• O₂ dependednt killing is the most effect mechanism - myeloperoxidase system
• HOCl generated by oxidative burst  in phagolysosomes destroys phagocytosed microbes
• O₂ is converted to O_2• by NADPH oxidase-oxidative burst
• O_2• is converted to H₂O₂ by superoxide dismutase (SOD)
• MPO cobines with H₂O₂ with Cl- to form HOCl
• O₂ independent killing is less effective than O₂ dependent killing 
• Lysozyme in macrophages
• Major basic protein in eosinophils
• Resolution
• Neutrophils undergo apoptosis and disappear within 24 hours after resolution of an inflammatory stimulus

• Leukocyte adhesion deficiency is mc due to an AT defect of integrins (CD18 subunit)
• Delayed separation of the umbilibal cord
• Increased circulating neutrophils-impaired adhesion of marginated pool of leukocytes
• Recurrent bacterial infections that lack pus

• Defect in lysosomal transport protein that affects the synthesis, maintenance and storgate of secretory granules in various cells
• Defect in microtubule function in monocytes and neutrophils so phagolysosomes cannot be produced
• AR
•  Increased risk of pyogenic infections
• Neutropenia due to intramedullary death of neutrophils
• Giant granules in leukocytes due to fusion on granules arising from the Golgi apparatus
• Defective primary hemostasia due to abnormal granules in platelets
• Albinism
• Perihperal neuropathy
• Bactericidal defect
• Increase in suspectibility to developing S. aureus infections
• Defects in chemotaxis

• Poor O₂ dependent killing
• NADPH oxidase defect (x-linked or AR)
• Leads to recurrent infections and granuloma foramtion with catalase positive organisms
• S. aureus
• Pseudmonas cepacia
• Serratia marcescens
• Nocardia
• Aspergillus
• Nitroblue tetrazolium test is used to screen for CGD
• Leukocytes are incubated with NBT dye which turns blue if NADPH oxidase is working properly
• If NADPH oxidase if deficient leukocytes are colorless

• Results in defective conversion of H2O2 to HOCl
• Increased risk for Candida infections
• Most patients are asymptomatic
• Nitroblue test is normal-respiratroy burst is intact

Macropphages

• Predominate after neutrophils
• Peak at 2-3 days after inflammation
• Dervied from monocytes in blood
• Arrive in tissue via margination, rolling, adhesion. and transmigration sequence
• Ingest organisms via phagocytosis and destroy phagocytosed material via enzymes and secretory granules
• Manage the next step of inflammation.  Outcomes include
•  Resolution and healing- anti inflammatory cytokines (IL-10, TNFβ) are produced by macrophages
• Continued acute inflammation- marked by the presistent pus formation. IL-8 from macrophages recruit additional neutrophils
• Abscess-acute inflammation surrounded by fibrosis.  Macrophages mediate fibrosis via fibrogenic growth factors and cytokines
• Chronic Inflammation-Macrophages present antigens to activate CD4 helper T cells which secrete cytokines that promote chronic inflammtion

• Characterized by the presence of lymphocytes and plasma cells in tissue
• Delayed response but more specific (adaptive immunity) than acute inflammation
• Stimuli include:
• Persistent infection: MC
• Infection with viruses, mycobacteria, parasites, and fungi
• Autoimmune disease
• Foreign material
• Cancer  

• Produced in bone marrow as progenitor T cells
• Further develop in the thymus where the T-cell receptor (TCR) undergoes  rearrangement and progenitor cells become CD4 helper T cells or CD8 cytotoxic T cells
• Use TCR complex along with CD3 for antigen surevillance
• TCR complex recognizes antigens presented on MHC molecules
• CD4 T cells- MHC class II
• CD8 T cells- MHC class I
• Activation of T cells require
• Binding of antigen/MHC complex
• Additional 2nd signal

• Extraceullar antigen (forgein protein) is phagocytosed, processed, and presented on MHC class II. 
• MHC class II is expressed by antigen presenting cells
• B7 on antigen presenting cells binds CD 28 helper T cells providing the 2nd activation signal
• Activated CD4 T cells secrete cytokines that "help" inflammation and are divided into two subets:
• TH1 subset secretes IL-2 (T cell growth factor and CD8 T cells activator) and INF-γ (macrophage activator)
• TH2 subset: secretes IL-4 (facilitates B-cell class switching to IgG and IgE, IL-5 (eosinophil chemotaxis and activation, maturation of B cells, to plasma cells, and class switching to IgA), IL-10 (inhibits TH1 subset)

• Intracellular antigen is processed and presented on MHC class I
• MHC class I is expressed by all nucleated cells and platelets
• IL-2 from CD4 Th1 T cells provides 2nd activating signal
• Killing of pathogens occurs via:
• Secretion of perforin and granzyme
• Perforin creates pores that allow the granzyme to enter the taget cell, activating apoptosis
• Expression of FasL which binds Fas on target cells and activates apoptosis  

• Immature B cells are produced in the bone marrow and undergo immunoglobulin rearrangements to become naive B cells that express IgM and IgD
• B cell antigen presentation to CD4 Tcells via MHC class II
• CD40 receptor on B cell binds to CD40L on CD4 T cells providing 2nd activation signal
• Helper T cells then secretes IL-4 and IL-5 that mediate B cell isotype switching, hypermutation and maturation into plasma cells  

• Subtype of chronic inflammation
• Characterized by granuloma which is a collection of epitheloid histiocytes, surrounded by giant cells and a rim of lymphocytes
• Noncaseating granulomas lack central necrosis
• Reaction to forgein material
• Sarcoidosis
• Chrons disease
• Cat scratch diease
• Caseating gramulomas exhibit central necrosis
• Characterisitic of TB and fungal infections
• Steps involved in Granuloma formation
• Macrophages process and present antigens via MHC class II to CD4 help T cells
• Interaction leads macrophages to secrete IL-12 inducing CD4 helper T cells to differentiate into Th1 subtype
• Th1 subtype secrete INF-γ which converts macrophages to epitheloid histiocytes and giant cells

• Developmental failure ofthe 3rd and 4th pharyngeal pouches
• Due to 22q11 microdeleton
• Presents with T cell deficiency due to lack of thymus
• Absent Thymic shadow on radiograph
• Hypocalcemia due to lack of parathyroids which presents as tetany
• abnormalities of heart, great vessels, and face
• CATCH 22
• Cardiac abnormalities-especially tetralogy of fallot
• Abnormal facies
• Thymic aplasia
• Cleft palate
• Hypocacemia/hypopapathyroidism
• 22-chromosome  

Severe Combined Immunodeficiency

SCID

• Defective cell mediated and humoral immunity
• Etiologies include:
• Cytokines receptor defects: cytokine signaling is necessary for proliferation and maturation of B cells
• Adenosine deaminase (ADA) deficiency- ADA is necessary to deaminate adenosine and deoxyadenosine for excretion as waste products.  Build up of adenosine nad deoxyadenosine is toxic to lymphocytes. MC
•  MHC class II deficiency- MHC II is necessary for CD4 Te cell activation and cytokine production
• Characterized by susceptibility to fungal, viral, bacterial, and protozoal infections including opportunistic infections and live vaccines
• Treatment is bone marrow transplat
• SCID patients do not reject allography

X-linked agammaglobulinemia

AKA

Bruton's agammaglobulinemia

• Complete lack of immunoglobulin due to disordered B cell maturation
• Naive B cells cannot mature to plasma cells
• Caused by mutated Bruton tyrosine kinase
• X-lined
• Presents after 6 months of life with recurrent bacterial infections
• Polio
• Coxsackievirus
• Giardia lamblia
• Maternal antibodies present during the first 5 months of life are protective
• Live vaccines must be avoided  

• Low immunoglobulin due to B cells not maturing to plasma cells or helper T cells defects
• Increased risk for bacterial infections
• enterovirus
• Giargia lamblia
• S. pneumonia
• Actinomyces israli
• H. influenzae
• S. aureus
• P. aeruginosa
• Increased risk for autoimmune disease and lymphoma  

• Low serum and mucosal IgA
• MC immunoglobulin deficiency
• Increased risk for mucosal infection especially viral
• Most patients are asymptomatic
• Anaphaylaxis if exposed to blood products that contain IgA 

• Characterized by elevated IgM
• Due to mutated CD40L (on helper T cells) or CD40 receptor on B cells
• Second signal cannot be delivered to helper T cells during B cell activation 
• Cytokines necessary for immunoglobulin class switching are not produced
• Decreased IgA, IgG, IgE
• Recurrent pyogenic infections due to poor opsonization especially at mucosal surfaces  

• Characterized by thrombocytopenia, eczema, and recurrent infections
• Due to mutation in WASP gene
• X-linked
• Progressive deletion of B and T cells
• Decreased IgM
• Normal IgG
• Increased IgA
• Increased IgE
• Associated risk of malignant lymphoma 

• C5-C9 deficiencies
•  Increased risk for Neisseria infections
• C1 inhibitor deficiency-results in hereditary angioedema which is characterized by edema of the skin and mucosal surfaces. 

• Anti-acetylcholine receptor
• Myasthenia Gravis
• Anit-basement membrane
• Goodpastures syndrome
• Anti-centromere
• CREST syndrome
• Anti-endomysial IgA, Anit-gliadin IgA, Anti- tissue transglutaminase IgA
• Celiac Diseas
• Anti-histone
• Druge induced lupus
• Anti-insulin and Anti-islet cell
• T1DM
• Anti-intrinsic factor adn Anti-parietal cell
• Pernicious anemia
• Anti-microsomal and Anti-thyroglobulin
• Hashimoto's thyroiditis
• Anti-smith and Anti-dsDNA
• SLE
• Anti A (RO) and Anti SS (La)
• Sjogrens syndrome
• Anti-topoisomerase
• Systemic Sclerosis
• Anti-myeloperoxidase
• Microscopic polyangiitis
• Anti-proteinase 3
• Wegener's granulomatosis
• Anti-mitochondrial
• Primary biliary cirrhosis
• Anti-ribonucleoprotein
• MCTD
• Anti-TSH receptor
• Grave's Disease

• Type IV (cytotoxic) and Type III (antigen-antibody complex) hypersensitivity
• W>M, Africian American MC
• Fever and weight loss
• Malar "butterfly" rash, especially upon exposure to sunlgiht
• Arthritis
• Pleuritis and pericarditis (involvement of serosal surfaces)
• CNS psychosis
• Renal Damage- Diffuse proliferative glomerulonephritis is the MC injury
• Endocarditis, myocarditis, pericarditis
•  Libman Sacks endocarditis is a classic finding and is characterized by small, sterile deposists on both sides of the mitral valve
• Anemia, thrombocytopenia, or leukopenia
• Renal failure and infection are MC causes of death
• Anti-smith and Anti-dsDNA
• Antiphospholipid antibody syndrome is associated with SLE 30% of cases

• Anti-histone antibody
• Hydralazine, procainamide, isoniazid
• Removal of drug results in remission

• Associated with SLE
• Characterizd by autoantibody against proteins bound to phospholipids
• Antibodies against anti-cardiolipin and lupus anticoagulant are the most common antibodies
• Leads to false positive syphilistest and falsely elevated PPT lab studies respectively
• Results in arterial and venous thrombosis including DVT, hepatic vein thromobosis, placental thrombosis (recurrent pregnancy loss) and stroke
• Requires life long anticoagulation  

• Autoimmune destruction of lacrimal and salivary glands
• Type IV mediated hypersensitivity with fibrosis
• Classically presents as dry eyes (keratoconjunctivitis), dry mouth (xerostomia)
• "Can't chew a cracker, dirt in my eyes"
• Anti-SS-A (RO) and Anti-SS-B (La)  
• Often assocaited with other autoimmune disease especially rheumatoid arthritis
• Increased risk for B cell (marginal zone) lymphoma, which presents as unilateral enlargement of the parotid gland late in disease course
• MC in older women (50-60)

• Autoimmune tissue damage with activation of fibroblasts and deposition of collagen (fibrosis)
• Women of child bearing age
• Systemic Sclerosis
• Almsot any organ can be involved
• Esophagus is commonly affected resulting in disordered motility- dysphagia for solids and liquids
• Anti-Topoisomerase (Scl-70) antibody
• CREST symptoms can also be present
• Respiratory interstitial fibrosis and can cause respitartoy failure
• CREST syndrome (limted sclerosis)
• C: Calcificaton/Anti-centromere
• R: Raynauds Phenomenon
• E: Esophageal dysmotility
• S: Sclerodactyly
• T: Telangiectasis of skin  

Mixed Connective Tissue Disease

MCTD

• Auto-imune mediated tissue damage with mixed features of SLE, sysyemic sclerosis, polymyositis
• Anti-ribonucleoprotein antibodies  

• Replacement of damaged tissue with native tissue: dependent on regenerative capacity of tissue
• Tissues are divided into three types based on regenerative capacity: labile, stable, and permanent
• Labile Tissue: possess stem cells  that continuously cycle to regenerate the tissue
• Small and large bowl (stem cells in mucosal crypts)
• Skin (stem cells in basal layer)
• Bone Marrow (hematopoietic stem cells)
• Stable Tissues are comprised of cells that are quiescent but can reenter the cell cycle to regenerate tissue when necessary:
• Liver
• Permanent tissues lack significant regenerative potential
• Myocardium
• Skeletal muscle
• Neurons  

• Replacement of damaged tissue with fibrous scar
• Occurs when regenerative stem cells are lost or when a tissue lacks regenerative capacity
• Granulation tissue formation is the initial phase of repair
• Consists of fibroblasts (type III collagen), capillaries (provided nutrients), and myofibroblasts (contract wound)
• Eventually results in scar formation in which type III collagen is replaced by Type I collagen
• Type III collagen is pliable and present in granulation tissue, embryonic tissue, uterus, and keloids
• Type I collagen has high tensile strength and is present in skin, bone, tnedons, and most organs
• Collagenase removes type III collagen and requires zinc as a cofactor  

• Mediated by paracrine signaling via growth factors
• Macrophages secrete growth factors that target fibroblasts
• Interation of growth factors with receptors results in gene expression and cellular growth
• TGF-α: epithelial and fibroblast growth factor
• TGF-β: Fibroblast growth factor and inhibits inflammation
• Platlet-derived growth factor: Growth factor for endothelium, smooth muscle, and fibroblasts
• Fibroblast Growth Factor: Important for angiogenesis and also mediates skeletal development  
• Vascular endothelial growth factor (VEGF) important for angiogenesis

Edges are not approximated

Granulation tissue fills the defect, myofibroblasts contract the wound and a scar forms

• Infection
• MC: S. aureus
• Vitamin C deficiency: important cofactor in hydroxylation of proline and lysine procollagen residues.  Hydroxylation is important for eventual cross-linking
• Copper Deficiency: Cofactor in lysyl oxidase which cross-links lysine and hydroxylysine to form stable colalgen  
• Zinc Deficiency: Cofactor for collagenase which replaces Type III collagen of granulation tissue with stronger Type I collagen
• Other causes of delayed wound healing include foreign body, ischemia, diabetes, and malnutirtion

Excess Production of scar tissue that is out of proportion to the wound

Characterized by excess Type III collagen

Genetic predisposition-African Americans

Classically affects earlobes, face, and upper extremities