Cellular, cell-mediated, delayed, or tuberculin-type reactions caused by sensitive T-cells after contact w/ a specific Ag
Circulating Ab/s are neither involved in nor necessary for development of tissue injury
Delayed type of hypersensitivity demonstrated by a positive tuberculin skin test
• Hypersensitivity to M. Tuberculosis is manifested by necrosis
Delayed type of hypersensitivity can be transferred by sensitized lymphocytes encounter Ag and release lymphokines – hence the term “cell-mediated”
Cellular infiltrate in a fully-developed delayed hypersensitivity reaction consists mainly of macrophages & lymphocytes
• Th1 cells and macrophages
Contact dermatitis
• Usually Latex is Type I (think allergic or atopic contact URTICARIA), but if the questions says it’s a TYPE IV rxn, which would mean Allergic contact DERMATITIS, then go with the following!!!
♦ Type IV reaction due to latex gloves, consists of Macrophages, Lymphokines, and T lymphocytes
Allograft rejection
• When a 1st rejected allograft is followed by a 2nd allograft from the same donor…the 2nd rejection occurs more rapidly than the 1st
♦ Hence, a reminder that you need presensitization
• Primary tissue transplant, such as allogenic skin, kidney or heart, are most commonly rejected due to
♦ Cell-mediated immune responses to cell-surface autoantigens
Similarities between Type I and IV???
• Complement OR Response after 24 hours???
Thymectomized and nude mice:
• Have reduced numbers of T-lymphocytes
• Can’t reject allografts
• Have reduced Ab production to most antigens – no helper Ts
• Have decreased or absent delayed type IV hypersensitivity
Classification of Hypersensitivity Reactions
Type Immunologic Mechanism Example
Type I (anaphylactic type):
Immediate hypersensitivity
IgE antibody mediated – mast cell activation &
degranulation
Hay fever, asthma, anaphylaxis, atopic dermatitis, eczema
Type II (cytotoxic type):
Cytotoxic antibodies
Cytotoxic (IgG, IgM) antibodies formed against cell surface antigens. Complement is usually involved
Autoimmune hemolytic anemias, antibody-dependent cellular cytotoxicity (ADCC), Goodpasture’s syndrome Type III (immune complex type):
Immune complex disease
Antibodies (IgG, IgM, IgA) formed against exogenous or endogenous antigens. Complement and leukocytes (neutrophils, macrophages) are often involved
SLE, rheumatoid arthritis, most types of glomerulonephritis, arthus rxn, serum sickness
Type IV (cell mediated type):
Delayed type hypersensitivity
Mononuclear cell (T lymphocytes, macrophage) w/
interleukin and lymphokine production
*Q answer: sensitized lymphocytes
Granulomatous disease (Tuberculosis, Sarcoidosis, Crohn’s, Fungus), contact dermatitis, graft rejection
Blood Group Ag/s (agglutinogens) on erythrocytes Antibodies (agglutinins) in plasma
O (universal donor) *none* Anti A & Anti B
A A Anti B
B B Anti A
AB (universal recipient) A & B (alloantigens – both A & B) *none*
Autoantibodies
Anti-nuclear antibodies (ANA) Systemic Lupus
Anti-dsDNA, anti-Smith Specific for Systemic Lupus
Anti-histone Drug-induced Lupus
Anti-IgG Rheumatoid arthritis
Anti-neutrophil Vasculitis
Anti-centromere Scleroderma (CREST)
Anti-Scl-70 Sclerderma (diffuse)
Anti-mitochondria 1ary biliary cirrhosis
Anti-gliadin Celiac disease
Anti-basement membrane Goodpasture’s syndrome
Anti-epithelial cell Pemphigus vulgaris
Anti-microsomal Hashimoto’s thryoiditis
INFLAMMATION & NECROSIS
Inflammation overview:
Exudative component:
Involves the movement of fluid, usually containing important proteins like fibrin and immunoglobulins
BVs are dilated upstream of an infection (causing redness and heat) and constricted downstream
Capillary permeability to the affected tissue is increased, resulting in a net loss of blood plasma into the tissue
• This gives rise to edema or swelling
The swelling distends the tissues, compresses nerve endings, and thus causes pain
Cellular component:
Involves the movement of WBCs from blood vessels into the inflamed tissue
The WBCs (leukocytes) take on an important role in inflammation
• They extravasate (filter out) from the capillaries into tissue & act as phagocytes
• They may also aid by walling off an infection and preventing its spread
If inflammation persists:
Released cytokines IL-1 & TNF will activate endothelial cells to upregulate receptors VCAM-1, ICAM-1, E-selectin, and L-selectin for various immune cells
Receptor upregulation increases extravasation of PMNs, monocytes, activated T-helper and T-cytotoxic cells, as well as memory T and B cells to the infected site
Inflammation can lead to anemia, because shift to making more inflammatory cells rather than RBCs
Cytokines:
Soluble mediators that play an important role in immunity
Small molecular weight peptides of glycopeptides
Many produced by multiple cell types such as lymphocytes, monocytes/macrophages, masts cells, eosinophils, even endothelial cells lining BVs
Each individual cytokine can have multiple functions
Depends upon the cell that produces it & the target cells upon which it acts (pleotropism)
Several different cytokines can have the same biologic function (redundancy)
Exert their effect:
1) on distant targets through the bloodstream (endocrine)
2) on target cells adjacent to those that produce them (paracrine)
3) on the same cell that produces them (autocrine)
Most important effect of most cytokines is paracrine & autocrine functions
Major functions appear to involve host defense or maintenance and repair of blood elements
Four major categories of cytokines:
Interferons:
A family of inducible glycoproteins produced by eukaryotic cells in response to viral infections
• The fact that eukaryotic cells produce interferon can be used to distinguish viral infections from other microbial assaults!!!!!
Interfere w/ virus replication
Act to prevent the replication of a range of viruses by inducing resistance
Elaborated by infected host cells that protect non-infected cells from viral infections
• Induce viral resistance in adjacent, non-infected cells
Do not block the entry of the virus into a cell, but rather prevent the replication of viral pathogens w/in protected cells
Are not antiviral antibodies
• Have no direct effect on viruses
• Antiviral action is mediated by cells in which they induce an antiviral state
Considered a non-specific innate resistance factor (as are lysozyme, complement, etc.)
• Interferon proteins do not exhibit specificity toward a particular pathogen
♦ Means interferon produced in response to one virus is also effective in preventing replication of other viruses
Alpha and Beta Inhibit viral protein synthesis
Gamma Increase MHC I expression and Antigen presentation in all cells
Tumor Necrosis Factors (TNF):
Injecting them into animals causes a hemorrhagic necrosis of their tumors
Secreted by activated macrophages – Easier to eat dead stuff
Interleukins (largest group of cytokines):
Fundamental function appears to be communications between (“inter-”) various populations of WBCs
Group of well-characterized cytokines produced by leukocytes & other cell types
Have broad spectrum of functional activities that regulate the activities & capabilities of a wide variety of cell types
Particularly important as members of cytokine networks that regulate inflammatory & immune responses
• Act as messengers between leukocytes involved in the immunologic or inflammatory response
Think mmmm, Hot T-Bone stEAk
IL-1: A macrophage-derived factor (mmmm)
Stimulates activites of T-cells, B-cells, & macrophages Stimulates IL-2 secretion
Pyrogenic (HOT)
IL-2: Produced by activated T cells (T- in T-bone)
Stimulates antigen-activated T helper & NK cells (as well as cytotoxic T cells) Also stimulates B cells
IL-3: T-cell product that stimulates the growth & differentiation of various blood cells in bone marrow (B in T-Bone)
Secreted by activated T cells
IL-4: Secreted by activated helper T cells & mast cells Stimulates B-cells
Increases IgG & IgE (E in stEAk)
IL-5: Secreted by activated helper T cells Promotes B cell maturation
IL-5 is a B-cell growth & differentiation factor
Increases IgA & synthesis of Eosinophils (A in stEAk)
Acute Phase cytokines IL-1, IL-6, and TNF alpha (secreted by macrophage to do a bunch of stuff)
IL-6, 7, 8, 10, 12: see Kaplan, p. 101 for thie summaries
Colony Stimulating factors (CSF):
They support the growth and differentiation of various elements of the bone marrow
Neutrophils: (aka polymorphonuclear leukocytes or PMNs)
Most numerous WBC (50–75%)
Increase dramatically in response to infection/inflammation
Fxns:
Phagocytosis of bacteria
Elaboration of proteolytic NZs
1st cells to infiltrate the inflammation site
PMNs kill by 1) toxic O2 metabolites & 2) digestive enzymes from lysosomal granules
Oxygen-dependent killing of bacteria by PMNs involves:
• Superoxide, Myeloperoxidase, Hydrogen Peroxide, NADP Dehydrogenase
• NOT collagenase
♦ Remember in Gingivitis you have lots of PMNs,
♦ In order get to PD, you need Collagenase, which comes from Lymphocytes!!!!
Enzymes include myeloperoxidase (azurophilic granules) & lactoferrin (specific granules)
Primary constituent of pus
Highly mobile cells – attracted to areas of inflammation by chemotaxis
They reach the tissues by diapedisis
Identify, attach to & begin engulfing the invading organisms in attempt to contain the infection
If infection continues, monocytes arrive (better engulfing ability)
NZs responsible for suppuration in an abscess are derived from PMNs
Inflammatory substances:
Process of attraction and recruiting cells in which a cell moves toward a higher concentration of a chemical substance
The Vasodilators:
Histamine
Bradykinin
C3 and C5 (via mast cells/Histamine)
Prostaglandins
Histamine:
Formed from histidine by decarboxylation
Released from the coarse cytoplasmic granules of tissue mast cells & basophils
In early stages of acute inflammation, histamine mediates the contraction of endothelial cells
Histamine is liberated by degranulation triggered by the following stimuli:
• Binding of specific Ag to basophil & mast cell MB-bound IgE
♦ TEST wording: Histamine release requires antibodies (IgE) attached to mast cells and reacting with antigen
• Binding of anaphylatoxins (C3a & C5a) to specific cell-surface receptors on basophils & mast cells
Release causes: increased capillary permeability, bronchial constriction, increased gastric secretion, and a drop in BP
Responsible for the principal symptoms of anaphylaxis
Serotinin has similar actions
Serotonin:
Also called 5-hydroxytryptamine
• Synthesized from the aa tryptophan by enteroendocrine cells in the gut & bronchi
Plays a role in temperature regulation, in sensory perception, and in the onset of sleep
Powerful vasoconstrictor Downstream??? And vasodilator
Stimulates platelet aggregation (blood clotting) – rls by platelets.
Largest amount is found in cells of the intestinal mucosa
• Smaller amounts in platelets & in CNS
In CNS:
• Acts as a neurotransmitter in the brain
• Inhibitor of pain pathways in spinal cord
• Lysergic acid diethylamide – interferes w/ action of serotonin in the brain
Secreted in tremendous quantities by carcinoid tumors (tumors composed of chromaffin tissue)
• Kaplan says, 5-HIAA is secreted, which is a metabolite of serotonin
Bradykinin:
Vasoactive kinin – potent vasodilator
Mediates vascular permability, arteriolar dilation, & pain
• Pain in inflamed tissue is associated with the Bradykinin mediator
Produced by the action of kallikrein (generated by activated Hageman factor, factor XIIa) on an alpha-2 globulin (kininogen)
Chemical mediator of acute inflammation that is generated through the activation of an enzyme precursor (Kallikerin) that requires activated Hageman factor
Hageman factor helps to create Bradykinin
May be involved in BP regulation
Arachidonic acid:
An unsaturated fatty acid generated by inflammatory cells and injured tissue
Major compound from which prostaglandins, prostacyclin thromboxanes, & leukotrienes are derived
Part of phospholipids in plasma MBs
When a neurotransmitter or hormone stimulates a cell, activating phosholipase A (a plasma MB enzyme)
• PLA splits arachidonic acid from the phospholipids
Different metabolic pathways utilize different enzymes that convert arachidonic acid into the different messengers:
• 1) Cyclooxygenase: prostaglandins, prostacyclins, & thromboxanes (NOT leukotrienes)
♦ Prostaglandins – chemical messengers present in every body tissue
♦ Act primarily as local messengers that exert their effect in the tissues that synthesize them
♦ *PGG2 is converted to PGH2, which is ultimately converted to TxA2
• 2) Lipooxygenase: leukotrienes, HETEs, diHETEs
Leukotrienes:
A group of compounds derived from unsaturated FAs (arachidonic acid & other polyunsaturated FAs)
Extremely potent mediators of immediate hypersensitivity reactions & inflammation
Leukotrienes C4, D4, & E4
• Collectively known as slow-reacting substances of anaphylaxis (SRS-As)
• Responsible for development of many symptoms associated w/ allergic-type reactions
100-1000x as potent as histamine or prostaglandins in constricting bronchi
In asthma, the allergic reaction occurs in the bronchioles of lungs
• The most important products released by mast cells are SRS-As (the 1° mediators of asthma)
• SRS-As causes bronchiolar smooth muscle spasms
Anaphylatoxins C3a & C5a – induce physiological response that results in BV dilation, hypotension, ↑ vascular permeability
Acute Inflammation:
The initial response of tissue to injury, particularly bacterial infections, involving vascular and cellular responses
What is involved in the early phase of wound repair?
Inflammatory bacteria and debris are phagocytosed and removed, factors are released that cause the migration and division of cells involved in proliferative stage
• Proliferative and Maturation are more in chronic
Three major phenomena:
1) Increased vascular permeability – tissue exudate forms
• Mean capillary pressure decrease and osmotic pressure decreases in acute inflammation
2) Leukocytic cellular infiltration – mainly PMNs via C5a & C3a
3) Repair – regeneration or replacement
Chemotactic accumulation of mononuclear cells which occurs at the sites where immune complexes were deposited is probably the result of C3 (only if C5a is not an answer)
Local signs:
Redness = rubor, Heat = calor, Swelling = tumor, Pain = dolor, organ dysfunction
Systemic effects:
Fever, Tachycardia, Leukocytsosis (esp. PMNs)
Vascular phase:
Vasoconstriction (temporary) – seen as blanching of skin
• What happens before Vasodilation in inflammation??? Vasoconstriction
• Only transient
Vasodilation – increased blood flow to infected area
• Happens immediately after vasoconstriction
• Done by Histamine, Bradykinin, and Serotonin
• The 1st vascular reaction (following transient vasoconstriction) to injury in the sequence of events in inflammation
Increased permeability – allows diffusible components to enter the site
• Congestion in the early stages of inflammation is caused by active hyperemia (NOT ischemia, venous dilitation, venous constriction, lymphatic obstruction)
Cells
• Basophils, Mast cells, Platelets – present in vascular phase – all release histamine
Vasodilation and increased permeability lasting for several days in an area of inflammation indicate
• Endothelial cell damage and dysfunction
Cellular phase:
Leukocytes (mainly PMNs) are the 1st defense cell to migrate to the injured tissue – chemotaxis
Leukocytes engulf particulate matter by phagocytosis
Engulfed matter becomes a phagosome – combines w/ lysosomal granules to form a phagolysome for digestion
Cells
• PMNs – predominate
• Macrophages – appear late & mark transition between acute & chronic inflammation
NOTE: Eosinophils – predominate in allergic reactions & parasitic infections
Chronic Inflammation:
Develops at a site of injury that persists longer than several days
Cells: Lymphocytes, Macrophages, and Plasma Cells – not PMNs or Mast Cells
Necrosis commonly occurs & recurs
EXs: chronic hepatitis, pyelonephritis, and autoimmune diseases
Granulomatous inflammation:
A subtype of chronic inflammation characterized morphologically by granulomas
Proliferative processes dominate (NOT exudation, transudation, and congestion)
Characterized by a circumscribed collections of lymphocytes, macrophages, epitheliod cells with a background of fibroblasts, capillaries, and delicate collagen fibers
EXs: TB, sarcoidosis, & silicosis
Vasodilation & ↑vasopermeability lasting several days in inflamed area indicate formation of granulation tissue
• Initial vasodilation of inflammation is due to serotonin, histamine, bradykinin
SIDENOTE
Chronic Granulomatous Disease
Hereditary disease where neutrophil granulocytes are unable to destroy ingested pathogens
Neutrophils normally require a set of enzymes to a reactive oxygen species to destroy bacteria after their phagocytosis
These NZs are called phagocyte NADPH oxidase complex, which is responsible for initiating the respiratory burst
SO in CGD, PMNs ingest baceria but then cannot kill them
• MOST infections are caused by Staph Aureus, or CATALSE + bugs
• Hence bugs that destroy the respiratory burst are left behind to cause chronic GD
Inflammatory Infiltrate
Fluids, PMNs, and Macrophages
Exudates:
Principally water – also contains nutrients, oxygen, Ab/s & WBCs
Characterized by being protein-rich, cell-rich, glucose-poor & has a high specific gravity (> 1.020)
First role – flush away any foreign material from site of injury
If fluid is cloudy/discolored – strong indication of infection
Acts as a carrier to bring fibrin, etc., to the site of injury
Acts as a carrier for leukocytes – provides oxygen/nutrients for ingestion of bacteria & debris
Nutrients are used by the new tissue to help in the generation of granulation tissue
Act as a lubricant, speeding up epithelial cell migration across wound surface to complete initial repair
Types of imflammatory exudates:
Suppurative
Purulent
Fibrinous
Pseudomembranous
Serous
• NOT Fibrous
Acute inflammatory exudates
Includes Plasma fluid, plasma proteins and WBCs
• NOT Plasma cells
Transudates:
Result from ↑ intravascular hydrostatic pressure or from altered osmotic pressure
Thin & watery – characterized by few blood cells, low protein content, & low specific gravity (< 1.020)
Differs from Exudate by having a lower protein concentration
Present in non-inflammatory conditions, such as cardiac failure
Most common acute inflammatory reactions
Contain large # of PMNs
Termed suppurative (produce purulent matter)
Suppuration is the result of tissue necrosis, proteolytic enzymes, WBCs, & fluid buildup
• NZs responsible for suppuration are found in the PMNs
• NOT the result of the presence of lymphocytes
Abscess:
Confined collection of pus, which consists of dead WBCs & necrotic tissue
Surrounded by a wall of proliferation fibroblasts (produce collagen) – body’s attempt to limit spread of infection
Cyst:
Abnormal sac w/in the body containing air or fluid
Lined w/ epithelium
Granulation Tissue:
Newly formed, highly vascularized CT associated with inflammation
Composed of:
Lymphocytes
Fibroblasts
Macrophages
Endothelial cells
Newly Formed Collagen
Capillary Buds
• NOT Giant cells, Nerve cells, or Epithelioid cells, or Plasma cells – these are Granul
omatous
Granuloma:
Differentiate!!!!
Central necrosis surrounded by macrophages, lymphocytes, plasma cells, and occasional giant cells
Nodular collections of epithelioid cells – specialized macrophages
Epithelioid cells are characteristic of granulomas (NOT granulation tissue)
Rim of lymphocytes, plasma cells, & fibroblasts surround the nodule of epithelioid cells
Produced by multinucleated giant cells (aka Langerhans giant cells & foreign body giant cells)
Multinucleated giant cells of the foreign-body type originate from fusion/division of mononuclear cells (macrophages)
Characteristically associated w/ areas of caseous necrosis – produced by infectious agents, particularly M. tuberculosis
Granulomatous inflammation is a subtype of chronic inflammation
Etiologic agents associated w/ granulomatous inflammation:
Infectious agents:
• Mycobacterial diseases – TB & leprosy
♦ Girl with ulcerated lesion on tongue has Langerhans cells and granulomatosis, what is the disease???
Tuberculosis Granuloma???
• Fungal infections – blastomycosis, histoplasmosis, & coccidiomycosis
• Spirochetes: T. pallidum, which causes syphilis
• Cat scratch disease – caused by Bartonella henselae
Foreign material – suture or talc
Sarcoidosis – unknown etiology, NON-caseating, NON necrotizing (whereas tuberculosis is caseation necrosis)!!!!!
Crohn’s disease – NON-caseating, NON-necrosis, granulomatous inflammation of the gut wall
Healing:
The restoration to integrity to an injured tissue
After the inflammatory phase, wound healing is accomplished by three mechanisms; contraction, repair, and regeneration.
In most instances, all three mechanisms occur simultaneously
Healing by 1st intention:
Healing by fibrous adhesion, w/out suppuration or granulation tissue formation
Occurs when wound margins are nicely apposed, such as in surgical repair of a surface wound
With well-approximated wounds, there is little granulation tissue & the final scar is minimal
Healing by 2nd intention:
Large wound defects
CT repair occurs when the wound is large & exudative – large amount of necrotic tissue & suppuration formed
Site fills in w/ a highly vascular, pinkish tissue known as granulation tissue
• This produces large, irregular scars
Uncomplicated healing of a wound by secondary intention, observed microscopically after 3 days is most likely to show...
• Ulceration of the epithelial surface
• NOT granulomatous inflammation, lack of acute inflammation, or keloid formation
Healing by 3rd intention:
Slow filling of a wound cavity or ulcer by granulations, w/ subsequent cicatrisation (the process of scar formation)
Which hormone establishes the greatest effect on granulation tissue in healing wounds?
Cortisone
Glucocorticoids have been shown to have the greatest effect on granulation tissue
Tensile strength of healing wound depends upon the formation of collagen fibers
Whether a wound heals by 1° or 2° intention is determined by the nature of the wound, rather than by the healing process
Keloids (cheloids):
A nodular, firm, movable, nonencapsulated, often linear mass of hyperplastic scar tissue, tender and frequently painful
Consist of wide, irregularly distributed bands of collagen fibers
Occur in the dermis & adjacent subcutaneous tissue, usually after trauma, surgery, a burn, or severe cutaneous disease such as cystic acne, and is more common in blacks
Tumor:
Growth of tissue that forms an abnormal mass
Caused by abnormal regulation of cell division
Generally provide no useful function & grow at the expense of healthy tissue
Necrosis:
Set of morphologic changes that accompany cell death w/in a living body
Differs from autolysis – a process of cell death outside a living body
May manifest in different ways, depending on the tissue or organs involved
Coagulative necrosis is the most basic and most common type of necrosis
When larger areas of tissues are dead, the tissue is called gangrene
Types Causes Most likely sites involved
Coagulation necrosis Ischemia (loss of blood supply) Heart & kidney (renal & cardiac infarcts) Liquefaction necrosis (infarct to brain) Suppuration, abscesses & ischemic CNS injury Brain or spinal cord
Caseous necrosis (Caseation) Granulomatous inflammation (typical of TB) Calcification and “Soapy” – Think Cheesy TB Lesion
Granulomatous inflammatory sites
Gangrenous necrosis Putrefactive bacteria acting on necrotic bowel or extremity
Lower extremities or bowel
Fibrinoid necrosis Immune-mediated vascular damage Arterial walls (RA, Scleroderma, RF) Fat necrosis Injured pancreas, trauma to adipose tissue Adipose tissue, pancreas
Basic Types of Necrosis
Basic Types of Necrosis