eRobbins Ch 4 - Diseases of the Immune System Flashcards
Innate Immunity
Natural/Native immunity
Mediated by cells/proteins that are always present & poised to fight
Immediate
Epithelial barriers (mucosa, skin, respiratory tract, GI tract)
Phagocytes (Neutrophils & Macrophages)
NK Cells
Compliment Cascade -> INFLAMMATION
Cytokine: IL 12, IFN-gamma, IL-23, TNF-alpha & IL-1
Adaptive Immuntiy
Acquired/Specific Immunity
Specialized APC
Humoral & Cell Mediated Immunity
B Lymphocytes = antibodies
T Lymphocytes = Helper or attack cells
Humoral Immunity
Antibodies bind to microbes & tag them for removal
Antibodies = Soluble proteins produced by B Lymphocytes/B Cells
Antibodies attack EXTRACELLULAR microbes in the blood (attach to outside of free floating microbes/peptides)
Effector cell = plasma cells that secrete antibodies
BACTERIAL
Cell-Mediated Immunity
Medicated by T Cells/Lymphocytes
Designed to phagocytose infected cells = VIRUSES
Cytotoxic T Lymphocytes (CTL) = Directly kill infected cells
Helper T Cells = activate phagocytes (to phagocytose microbes & then kill) via cytokines
Effector Cell = CTL mostly, but also Helper T Cells
Naive T cells are activated by antigen & co-stimulators to proliferate & differentiate
T Lymphocytes
Thymus derived
1) Memory Cells
2) Effector Cells = CD8 & CD4
CTL (CD8 + MHC I) = that kill
Helper T cells (CD4 + MHC II) = secrete cytokines that increase B cell response/antibody production & phagocytosis
MHC
presents peptide fragment to CD4/CD8 for recognition
to mature T Cell
MHC Restriction
a T cell will recognize a peptide antigen only when it is bound to a host body’s own MHC molecule
won’t recognize an MHC peptide complex that’s not the own bodies
T Cell Receptor (TCR)
heterodimer with a disulfide linked alpha & beta chain
(analogous to BCR’s Ig alpha & beta)
5 invariant polypeptide chains (3 CD3 proteins & 2 other chain - weird greek letter) = signal transduction
B Cell Receptor (BCR)
Membrane IgM or IgD & associated signal proteins Ig alpha & beta
CD21 = CR2 receptor for complement protein that promotes B Cell activation & attached to BCR
(CR2 = Type 2 Complement Receptor)
CD4+
“Helper” T Cells
Secrete cytokines that:
1) Increase B cell response/antibody production
2) Recruit macrophages for phagocytosis
Release IFN-gamma, IL-2, IL-4, IL-5
IL-2
HIV = no CD4
CD8+
“Cytotoxic T Lymphocytes (CTL)
CTL (CD8 + MHC I) = that kill
Kill cells that express foreign antigen IN THEIR CYTOPLASM
Secrete Cytokines that directly kill
VIRAL
Natural Killer (NK) Cells
Innate Immune System lymphocyte
Not variable, very general
Inhibitory or Activating:
- Inhibitory = recognized self MHC class I & tells to not attack
-default is to stay inhibitory; but then
become activated
- Activating = recognizes expressed/up-regulated on stressed/infected/DNA damaged cells -> then cells are eliminated)
Kills by tagging & then gets opsonized/phagocytosed
CD28
Cluster of Differentiation 28
Co-stimulator protein on TCR complex
Stimulatory signals required for T cell activation and survival
MHC
MHC for humans = HLA (Human Leukocyte Antigen) Complex
Chromosome 6 & HIGHLY polymorphic
MHC Class I
CD8+ Cytotoxic T Lymphocytes
HLA-A, HLA-B, HLA-C
Structure:
1 alpha chain with 3 domains
1 Beta microglobulin
Peptide in cleft is from proteins synthesized int he cytoplasm
VIRAL
longer peptide because open ends?
Binds peptides that are 8-10 AA in length
MHC Class II
CD4+ “Helper T Cell”
HLA-D
Structure: Heterodimer
1 Alpha Chain with 2 alpha domains
1 Beta Chain with 2 beta domains
Binds peptides that are 15-24 AA in length
B Lymphocytes
Memory Cells
Effector Cells = produce Antibodies
Dendritic Cells
Major APC
Interdigitating DC - lots of MHC I & costimulatory molecules to capture & present to T CELLS
Langerhans cells = Under epthelia
Follicular DC (FDC)= located in germinal centers of lymph FOLLUCLES
- bear receptors for Fc tails of IgG & complement proteins that work to trpap antigens bound to antibodies/complement (antigen filter)
- Then present to B CELLS
APC
Captures microbial antigens & displays them on membrane to lymphocytes
Dendritic Cells
Macrophages
B Cells -> Helper T Cells
Protein antigens are proteolytically digested & then displayed on MHC clefts
IgM
membrane bound Ig/Antibody expressed on cell’s surface
Forms the B Cell Receptor (BCR)
IgA
Secreted in mucosal tissues
Neutralizes microbes in the lumen of mucosal tissues (respirator & GI tracts)
IgE
Surface of mast cells & Eosinophils
Coats helminthic parasites & kills them
TH2 cells
IgD
expressed on the surface of B Cells
NOT secreted
Primary/Generative Lymphoid Organ
Bone Marrow & Thymus
Secondary/Peripheral Lymphoid Organ
adaptive immune response develops & lymphocytes mature/specialize
IFN-gamma
ACTIVATES macrophages
Released by activated macrophages & DC, endothelial cells, lymphocytes & mast cells
secreted by NK cells
early innate immune response
activates macrophages, stimulates B cell antibody production, activates complement & coats microbes for phagocytosis
IL-2
Activates T Cells & tells to proliferate & differentiate
Regulate lymphocyte response & effector functions in ADAPTIVE immunity
Proliferation & Differentiation of lymphocytes
growth factor that acts on CD4+ & stimulates proliferation
Helper T cell Cubsets
TH1
- Recognize antigens of microbes ingested by phagocytes & activates phagocytes to kill microbes
- produce IFN-gamma (activates macrophages, stimulates B cell antibody production, activates complement & coats microbes for phagocytosis)
TH2
- Activate Eosinophils
- Think allergies & asthma
- Produces IL-4 (stimulates B cell differentiation into IgE secreting plasma cells)
- Produces IL-5 (activates eosinophils)
- Produces IL-13 (activates mucosal epithelial cells to secrete mucus & expel microbes)
TH17
- Enhance leukocyte recruitment & stimulate inflammation
- Produces IL-17 (recruits neutrophils & promotes inflammation)
IL 12
early innate immune response
Released by activated macrophages & DC, endothelial cells, lymphocytes & mast cells
IL-23
early innate immune response
Released by activated macrophages & DC, endothelial cells, lymphocytes & mast cells
TNF-alpha
chemoattractant
early innate immune response
Released by activated macrophages & DC, endothelial cells, lymphocytes & mast cells
IL-1
chemoattractant
early innate immune response
Released by activated macrophages & DC, endothelial cells, lymphocytes & mast cells
IL-4
Regulate lymphocyte response & effector functions in ADAPTIVE immunity
Proliferation & Differentiation of lymphocytes
stimulates B cell differentiation into IgE secreting plasma cells
IL-5
activates eosinophils
Colony Stimulating Factor
stimulates hematopoiesis
Increase output of Leukocytes from bone marrow
CD40 & CD40Ligand
Co-stimulatory protein on APC ( B Cells & Macrophages)
CD40 & CD40 Ligand bind & activate APC
IL-13
Activates mucosal epithelial cells to secrete mucus & expel microbes
IL-17
recruits neutrophils & promotes inflammation
released by TH17
Affinity maturation
process of Helper T cells that stimulate the production of antibodies with higher antigen affinity
refinement of antibody production
IL-22
a
TGF - Beta
a
IL-23
a
IL-6
a
GO BACK THROUGH ALL CYTOKINES*
IgG
Antibodies coat/opsonize microbes & target them for phagocytosis by Neutrophils & macrophages
Express Fc tails
Activates Complement system by Classical Pathway
Stimulates by IFN-gamma & TH! cells
Actively transported across placenta to create passive immuntiy
Immediate (Type I) Hypersensitivity
Hallmark - Production of IgE antibodies
vascular permeability & smooth muscle contraction
Disorders:
Allergy, asthma, allergic rhinitis, conjunctivitis Hives/uticaria, Anaphylaxis, atopy
Mechanism: Activation of T2 helper cell & antibody class switching -> IgE
MEDIATORS OF TYPE I RESPONSE
- CD4+ T helper cell subtype: “Th2 cell”
- IL-4 promote switching of B cells from IgM to IgE production and further Th2 development
- IL-5 induce expansion and activation of eosinophils
- IL-13 promote switching of B cells from IgM to IgE production and stimulate mucus secretion by epithelial cells
3 groups of mediators released:
Immediate: vasoactive amines released from mast cells
1) Vasoactive Amines released/degranulate (histamine, proteases, ECF/NCF) (EARLY)
2) Membrane Phospholipids/lipid mediators (AA pathway = Prostaglandins & Leukotrienes)
Late Phase: cytokines/inflammatory response
3) Cytokine secretion
- > immediate release from mast cells & later recruits inflammatory cells (LATE) - TNF; amplifying TH2 response
Symptoms:
vascular dilation, edema, smooth muscle contraction, mucus production, inflammation
EOSINOPHILS - late phase
*Eosinophil chemotactic factor (ECF) produced by mast cells recruit eosinophils to tissue site.
*IL-5 produced by Th2 cells promote growth and activation of eosinophils.
*Secrete major basic protein and eosinophil
cationic protein toxic to epithelial cells
*Produce leukotriene C4 and platelet
activating factor (PAF) that directly activate
mast cells
Antibody-mediated (Type II) Hypersensitivity
IgG & IgM production
*Specific antibody binding to cell surface antigen results in injury to cell via variety of potential mechanisms
Disorders:
Autoimmune, hemolytic anemia (Fetal Rh attack), Good pasture syndrome (Table 4-3)
Mechanism:
1) Opsonization/phagocytosis (Fetal Rh factor); Antibodies IgG & IgM bind to antigen on cell surface (either intrinsic (auto antigen) or exogenous (foreign) [e.g. drug] that attaches to cell surface) =>
2) Complement & Fc receptor mediated inflammation (Good pasture - Kidney & lung functions)
degranulation of mast cells => recruitment of leukocytes
3) Antibodies bind to ACh receptor & stimulate/block signaling
(block = Myasthenia Gravis; stimulate = Graves disease/hyperthyroidism)
Symptoms:
variety - see Table 4-3
Phagocytosis & lysis of cells, inflammation, functional derangements without cell/tissue injury
Immune complex-mediated (Type III) Hypersensitivity
- Soluble antigen & free floating complex, activates complement & inflammatory cascade
Disorders:
- Vasculitis, lupus, glomerulonephritis, serum sickness, Arthus reaction
- Lots of “-itis”es
Mechanism:
- Antibody binds to circulating antigens to form immune complex
- Immune complexes deposit in preferred tissue sites and elicit inflammatory response:
- Blood vessel wall (vasculitis)
- Glomeruli (glomerulonephritis)
- Joints (arthritis) - Immune complex activates complement to recruit neutrophils; mechanism of injury similar regardless of tissue site
- Large IC (Immuno Complex) - rapidly cleared because so big/obstructive
- Small - poorly cleared, circulate, & deposit in tissues (filters); deposit inflammatory mediators -> causing inflammation
Symptoms:
Abnormal & location specific Inflammation
Inflammation, necrotizing vasculitis/fibrinoid necrosis
Cell Mediated (Type IV) Hypersensitivity
T Cells gone awry
Disorders: Contact dermatitis/poison ivy, MS, DM1, TB
Mechanism:
- CD4+ T cells react to foreign or self-antigens, release cytokines and differentiate into:
-Th1 cells (IFN-γ TNF-α); macrophage activation
-Th17 cells (IL-17, IL-22): neutrophils activation
- CD4+ T cells recruit CD8+ T cells [cytotoxic T
lymphocytes (CTL)]
2 Types:
1) DTH = CD4 mediated
S/s: Contact dermatitis
2) Cellular cytotoxicity = CD8 mediated
S/s: CD8+ attacking own cells (MS = myelin sheath, DM1 = Islet cells )
- Type I diabetes mellitis: T cells react with antigens of pancreatic islet β cells (insulitis)
- Multiple sclerosis: T cells react with antigens in CNS myelin (perivascular inflammation in white matter and demyelination)
- Rheumatoid arthritis: T cells react with antigens in joint synovium (chronic arthritis)
- Contact sensitivity: T cells react with antigens of poison ivy and poison oak (dermatitis with blisters)
Symptoms: perivascular cellular infiltrates, edema, granuloma formation & cell distruction
Sjogren Syndrome
destroy the exocrine glands, specifically the salivary and lacrimal glands
xerostomia (dry mouth) keratoconjunctivitis sicca (dry eyes)
Primary Sjögren’s = occurs by itself
Secondary Sjögren’s = another connective tissue disease is present (RA & SLE)
Mikulicz Syndrome
Benign enlargement of the parotid and/or lacrimal glands
Sometimes, but not always, associated with Sjögren’s syndrome
Scleroderma/Systemic Sclerosis
Characterized by thickening of the skin caused by accumulation of collagen, and by injuries to the smallest arteries
Limited cutaneous scleroderma = skin on the face, hands and feet
Diffuse cutaneous scleroderma = covers more of the skin, and is at risk of progressing to the visceral organs, including the kidneys, heart, lungs and gastrointestinal tract
CREST syndrome C = Calcinosis R = Raynaud's phenomenon E = Esophageal dysfuction S = Sclerodactyl (skin thickening) T = Telangiectasias (dialated capillaries on face, hands, mucous membranes)
Amyloidosis
amyloidosis is a non-specific term that refers to a number of different diseases
Amyloids are proteins whose secondary structure changes, causing the proteins to fold in a characteristic form, the beta-pleated sheet
Normally soluble proteins=> amyloids, they become insoluble and deposit in organs or tissues, disrupting normal function
Congo Red => Apple green under polarized microscope
Systemic = more than one organ system Localized = 1 organ system/tissue type
Primary = disordered immune cell function Secondary/Reactive = complication of some other chronic inflammatory/tissue-destroying disease
Systemic Lupus Erythematosus (SLE)
Immune system attacks healthy tissues
Remissions
Characteristic rash - thought to be from wolf bite
Systemic = Type II & III Hypersensitivity Discoid = skin lesions Drug-induced = chronic use of certain drugs Neonatal = infant from mother with SLE
Polymyositis/Dermatomyositis
Polymyositis = Inflammation of many muscles
Dermatomyositis = Inflammation of muscles & skin
follows after pregnancy
Side effect of Statins
Fc Receptor
Protein that binds to antibodies and is attached to infected cells or invading pathogens
Stimulates phagocytic or cytotoxic cells to destroy microbes
On:
B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils, eosinophils, basophils and mast cells
