BLD 204 Exam 2

IgG

- neutralize toxins & opsonize bacteria
- monomer
- 70-80% of plasma Ig
- crosses placenta (mom to fetus)

IgM

- largest (pentamer)
- first after immunization
- 10 binding sites -- good for repeating epitopes

IgA

- dimer
- mucosa, tears, sweat
- stops bacteria & viruses from entering epithelium

IgE

-Fc binds to receptors on mast cells (release histamine & leukotrienes)
- calls eosinophils
- involved in hypersensitivity

IgD

- present on some B cells
- helps with antigen recognition/activation with IgM

Innate Immunity Cytokines

- TNF
- IL-1
- chemokines

Adaptive Immunity Cytokines

- IL-2,-4,-5,-6,-10
- IFN-gamma

Hematopoiesos Cytokines

- IL-3
- GM-CSF
- G-CSF
- M-CSF

Isotype (Class) Switching

- Constant (C) region of heavy chain switches to different Ig
- VDJ stays the same, antigen specificity stays the same
- IgG (Th1)
- IgE (Th2)
- IgA

B Cell Activation: T Independent

- multiple copies of antigen present close together and are engaged by multiple BCR
- stimulates proliferation of B cell line
- B cells differentiate to plasma cells & produce antibodies

B Cell Activation: T Dependent

- need CD4 T helper cells
-B cells act as APCS -> ingest and chopped up antigen and present on cell surface as MHC II
- CD4+ T cells recognize on MHC II and produce cytokines that activate B cells (CD40/B7 on T and CD40L/CD28 on B)

Cytokines for B Cell Proliferation

- IL-2, IL-4

Cytokines for B Cell Differentiation

- IL-4, IL-6, IL-10, IFN-gamma

Antibody Functions

- neutralize bacteria & toxins
- opsonization
- ADCC (antibody dependent cell-mediated cytotoxicity)
- activate complement

Type I Hypersensistivity

ALLERGY
- Th2, IgE, Mast cells
- First exposure: Th2 cells activated and class switch to IgE, IgE then binds to mast cells via Fc region
- Second exposure: antigen binds to IgE on mast cells and causes degranulation of histamine, leukotriens, prostaglandins, mast cells also release IL-4,-5 (amplify IgE response) and IL-13 (mucus release)

Cytokines that amplify IgE

- IL-4, IL-5

Type II Hypersensitivity

ANTIBODY MEDIATED
- antibody against tissue components
- antibody binds to epitope --> phagocytosis, complement activation, antibody dependent dysfunction

Type II Hypersensitivity Outcomes

- immune hemolysis: hemolytic disease of newborns due to Rh
- drug-induced: drugs = carriers for hapten, unmask something an antibody can bind
- Grave's Disease: hyperthyroidism (antibodies bind to TSHR instead of TSH and cause more thyroid activity/hormones)

Type III Hypersensitivity

AB/AG COMPLEXES
- complexes deposited in tissues
- causes inflammation (10 days after antigen or so) -- complement activation, vasoactive amines, platelet aggregation

Type III Hypersensitivity Examples

- Glomerulonephritis
- arthritis in joints
- serum sickness

Type IV Hypersensitivity

CELL MEDIATED
- Sensitized T cell do damage
- Delayed Type Hypersensitivity (DTH) --12-48 hours after exposure, T effector cells secrete cytokines
-prolonged response = granulomatous inflammation
- cytotoxic lymphocytes kill cells and show antigen
- Rejection of transplants

Type IV Hypersensitivity Outcomes

- tissue/organ rejection
- granulomatous inflammation
- inflammation --> contact dermatitis

6 mechanisms for loss of self tolerance (autoimmunity)

1) previously secluded tissue proteins exposed
2) alteration of tissue antigens -- injury, infection, drugs
3) exposure to shared determinants -- exogenous antigen similar to self antigen
4) impaired T cell recognition
5) genetics
6) autoimmune disease

Describe the Ag, etiology, pathogenesis, and whether Systemic Lupus Erythematosus (SLE) is mainly humoral or cell mediated:

- most common in young females
- autoantibodies --> ANA (antinuclear antibodies)
- immune complex deposition --> organ damage
- pathogenesis: butterfly rash, pain in joints, fever, chest pain

Describe the Ag, etiology, pathogenesis, and whether Rheumatoid Arthritis (RA) is mainly humoral or cell mediated:

- mainly join pains
- immune complex deposition --> damage from cytokines
- 3-5X more likely in women 20-40 years old
- genetic and environmental factors play a role

Describe the Ag, etiology, pathogenesis, and whether Hashimoto's Thyroiditis is mainly humoral or cell mediated:

- autoantibodies to thyroid tissues --> destruction of thyroid epithelial cells
- CELL MEDIATED: CD8+ cell death, ADCC
- symptoms: enlarged thyroid, hypothyroidism
- middle-aged women

Define Immunodeficient

1) inadequate response to antigen
2) excess or inappropriate response --> hypersensitivity
3) inability to identify self v. non-self: autoimmunity
4) neoplasms of immune cells

Primary Immunodeficiency vs. Secondary Immunodeficiency

- Primary: congenital, genetically determined, rare, appears early in life
- Secondary: acquired, secondary to therapy (transplant) or disease (HIV)

Afferent vs Efferent Immune Deficiencies

- Afferent: antigen presentiation and recognition
- Efferent: T cell activation and antibody production

Discuss the etiology and pathogenesis of acquired immunodeficiency syndrome (AIDS):

- viral infection: HIV1 and HIV2
- depletion of CD4 lymphocutes -> severe immunosuppresion -> opportunistic infections, neoplasms
- spread through blood & body fluids that contain virus
-Major targets: CNS and Immune system
- Problems: loss of CD4 T cell, defective DC & macrophage function, damage to lymphoid tissue

Discuss the etiology and pathogenesis of Severe Combined Immunodeficiency (SCID):

- no antibody & no cell mediated response --> severe recurrent infections due to pathogens (no T and B cells)
- ADA deficiency --> build up of A and dATP --> lymphocyte death & decrease in DNA synthesis
- common gamma chain defect: defective receptors for cytokines --> decrease proliferation of T and B precursors
- Treatment: bone marrow transplant

Discuss the etiology and pathogenesis of DiGeorge Syndrome:

- thymatic development defect
- genetic defect: C22
- sometimes better by age 5
- viruses and intracellular bacterial infections

Discuss the etiology and pathogenesis of Bruton Disease:

- X-linked agammaglobulinemia (little/no B cells)
- Pre-Bs fail to mature and get blood
- low plasma Ig

Describe the physical characteristics of an organ that has significant amounts of amyloid deposition:

- larger, paler, firmer

Describe the microscopic features and staining properties of an organ that has significant amounts of amyloid proteins:

- lack of structure; EM shows bundles of fibrils
- pinkish when stained with eosin dye
- binding red cargo dye

Define primary amyloidosis:

- deposition without disease
- monoclonal plasma cell proliferation
- multiple myeloma

Define secondary amyloidosis:

- follows identifiable disease
- chronic inflammation
- Rheutoid Arthritis (RA)

State the origin of amyloid proteins in Immune Origin Amyloidosis:

- precursor protein: Ig light chain (usually lambda, changes from alpha helix to beta sheet)
- AL amyloid light chain type
- source: single B lineage clone

State the origin of amyloid proteins in Hemodialysis-Associated Amyloidosis:

- precursor protein: B2 microglobulin
- source: shed from cell membranes due to dialysis
- AB2M type
- outcome: carpal tunnel syndrome

State the origin of amyloid proteins in Reactive Systemic Amyloidosis:

- precursor: SAA --> produced by liver, increase inflammation, signals for upregulation (IL-1,-6, TNF)
- symptoms: systemic deposits, kidney, liver, adrenal glands, main cause f death = renal failure

What are the Disease Associations with Reactive Systemic Amyloidosis:vi

- Infections: TB, syphilis, leprosy
- Unknown etiology: RA, UC, Crohn's
- Paraplegia: UTIs
- neoplasms: renal adenocarcinoma

State the origin of amyloid proteins in Hereditary Systemic Amyloidosis:

- precursors: transthyretin with mutation
- source: plasma
- normally beta sheets, but withmutate = b sheets wtih fibrils

- types: nephropathic & cardiopathic
- nephropathic: Familial Medit. Fever
- precursor: SAA
- treatment: 1-2mg colchicine

State the origin of amyloid proteins in Endocrine-Related Amyloidosis:

- precursor: short portion of calcitonin
- thyroid carcinoma & pancreatic islet cells in type II diabetes


- intracerebral
- alzheimers (A4)
- prion associated diseases -> prion protein

State the relationship of SAA with inflammation:

SAA follows inflammation which increases 1000 fold

State the role of the MHC in the immune response:

- MHC expressed the antigen for immune cell activation

Define Autograft:

- tissue from one part of both to another (self)

Define Isograft:

- tissue from twin to another

Define Allograft:

- tissue from one relative to another (same species)

Define Xenograft:

- cross species
- pig heart -> human body

State the role of MHC in transplantation:

- Host T cell & Donor APC can activate each other depending on MHC/HLA

State the role of the histocompatibility laboratory:

Typing HLA Genes:
- serological testing: look for Ab/Ag between donor and recipient; HLA genes on surface
- molecular testing: look for differences in DNA in HLA genes; PCR & probe
- cellular testing: mix lymphocytes from donor and recipient; positive rxn --> proliferation, cell-mediated toxicity, cytokine production

Describe the histocompatibility testing needed for the major transplanted organs vs bone marrow:

Solid Organs
- 6 antigen matched
- ABO compatibility

Bone Marrow
- 10 antigen matched
- ABO compatibility

Describe and recognize the major types of rejection episodes:

- Hyper acute
- acute
- chronic

Describe hyper acute transplantation rejection with regard to the immune response, time course, and histologic appearance:

- time course: minutes to hours
- response: performed antibodies in recipient plasma bind to graft endothelium
- fibrinoid necrosis, ischemia, thrombosis

Describe acute transplantation rejection with regard to the immune response, time course, and histologic appearance: [cellular vs. humoral]

- time course: 7-10 days (early), 11 days-6weeks (late)

Cellular Immunity
- time: within first months
- CD4 & CD8 cells in organ with edemia, mild hemorrhage
- renal problems
- distinguish from drug toxicity from cyclosporine

Humoral immunity
- antidonor antibodies
- necrosis neutrophils, complement, Ab, fibrin, thrombosis

Describe chronic transplantation rejection with regard to the immune response, time course, and histologic appearance:

- time: months to years after transplant
- antibodies bind to HLA on endothelium
- arterial symptoms: thickening
- kidneys: glomerular damage, rising creatinine

Describe Graft Versus Host Disease (GVHD):

Competent donor T cells transferred into immunocompromised host
- both CD4 & CD8 respond to recipient tissues as foreign
- inflammation & cell death

Acute
- days/weeks
- epithelial necrosis in liver, skin, gut
- symptoms: jaundice, bloody diarrhea, cutaneous rash

Chronic
- follow acute or just appears
- skin lesions, autoimmune-like symptoms

Name the major anti-rejection drugs and describe their modes of action:

-Azathioprine (T cell mediated)
- Cyclosporin A (Inhibit clonal CTL expansion)
- Tacromilus (T helper lymphokine production)
- Rapamycin (IL-2 receptor interference)
- Biologics (monoclonal Ab against T helpers)

Anti-rejection drugs: Side effects

- nephrotoxicity
- risk of infection
- hypertension
- hyperlipidemia
- neoplasia (tumors & lymphomas)

List the major components involved in hemostasis and describe the function of each:

- vascular wall: endothelium
- platelets
- coagulation cascade

What are the 3 levels of the Blood Vessel:

- intima: inner layer - lumen, empty space
- media: middle - luminal lining/endothelial layer
- adventitia: outer - smooth muscle & ECM

Define Hydrostatic Pressure

- pressure that blood exerts on the vessel

Define Plasma Colliod Osmotic Pressure

- pressure exerted by different concentrations of molecules inside and outside of vessel

Define Interstitial Fluid Pressure

- pressure exerted by interstitial fluid in the space outside of the vessel

Define hemothorax

- collection of blood in the lining of lungs (pleural sacs)

Define hemopericardium

- collection of blood in the pericardial sacs of the heart

Define hemoperitoneum

- blood accumulates in space between inner abdominal wall & internal abdominal organs

Define petechiae

- small red or purple dots caused by bleeding into skin

Define purpura

- rash of purple spots caused by internal bleeding of small blood vessels

Define ecchymoses

- discoloration of skin resulting from bleeding underneath (bruise)

List two agents capable of initiating formation of a clot

- thrombin & coagulation factors? (Hageman factor, Xa)

Describe the five steps of hemostasis

1) Vasoconstriction: endothelin allows constriction
2) Platelet Plug: initial plug = primary hemostasis, damage to epithelial layer = expose ECM - facilitates platelet adhesion, activation, aggregation
3) Coagulation Cascade Activation: tissue factor + Factor VII = thrombin activation
4) Stable Clot Formation/Secondary Hemostasis:
thrombin -> cleave fibrinogen -> fibrin clot
thrombin -> activate platelets -> reinforce plug
5) Limitations of Clotting: fibrinolysis, TTPA (tissue type plasminogen activator), plasminogen cleaved into plasmin which degrades fibrin

List procoagulant and anticoagulant functions on endothelium

Procoagulant
- vWF activation of platelets
- TF activation of coagulation cascade
- plasminogen activator inhibitor

Anticoagulant
- inhibit platelets by hiding ECM
- inhibits coagulation factors with heparin-like molecules, thrombomodulin, TFPI
- fibrinolysts, TTPA

Compare & contrast primary hemostasis and secondary hemostasis

Primary hemostasis
- initial platelet plug

Secondary hemostasis
- platelet contraction, formation of fibrin clot

Detail the actions of adhesion, release, aggregation, and interaction with the clotting system that platelets provide to hemostasis, including the result if any of the processes or integral components are lacking:

Platelet Adhesion
- Gp1b on platelet binds to vWF on ECM

Platelet Activation
- granules release upon binding
- Ca++ -> coagulation factors
- ADP -> platelet activator
- TxA2 -> activates more platelets (AA metabolism)

Platelet Aggregation
- fibrinogen binds to GpII/IIa to form bridges
- thrombin activates PAR and converts fibrinogen to fibrin

List 3 functions of thrombin

1) activates platelet aggregation and endothelial cells
2) generates fibrin
3) activates leukocytes

3 Types of Anticoagulants naturally in the body

Antithrombin
- inhibit thrombin: IXa, Xa, XIa, XIIa

Protein C & S
- Vit K dependent, act on Va, VIIIa

TFPI
- tissue factor pathway inhibitor

State how thrombi can be lysed

- Fibrinolytic cascade ends with plasmin degrading fibrin
- plasminogen activator inhibitors block fibrinolysis

Explain what causes fluid to leave the vasculature:

- increased intravascular hydrostatic pressure
- increased colloid osmotic pressure in extravascular environment (high concentration outside)

Explain what causes fluid to stay in the vasculature:

- osmotic pressure of plasma proteins, especially albumin
- selective permeability of endothelium
- tissue tension
** normal net loss from vasculature returns through the lymph system

Vascular Smooth Muscle Cells

- normal repair and pathology
- capable of proliferation, upregulation of ECM components and growth factors & cytokines
- vasoconstriction or vasodilation

Endothelium Functions

- maintain thrombosis balance
- oxidize LDL
- modulate inflammation
- influence growth of other cell types
- modulate vascular permeability
- influence smooth muscle behavior

Endothelial Cell Activation

- change shape
- produce adhesion molecules
- produce cytokines & coagulation influencing factors
- too long an exposure to inducers = dysfunction and damage

Endothelial Cell Activation Inducers

- bacteria & viruses
- Pro-inflammation cytokines
- stress
- lipids
- complement
- hypoxia

Regulators of Smooth Muscle: keep quiet

- NO
- TGF-alpha
- Heparan sulfate

Judging Clinical Significance

- volume
- rate
- general health of significant

Differentiate between active hyperemia and congestion (passitve hyperemia)

Active Hyperemia
- football game: lots of flow in, normal flow out

Congestion
- construction: normal flow in, less flow out

Differentiate between hyperemia & hemorrhage

Hyperemia
- excess amount of blood in vessels supplying and organ or part of body

Hemmorhage
- escape of blood from ruptured blood vessel, especially when profuse

Define edema

- abnormal accumulation of fluids in extravascular compartments

Define ascites

- fluid in abdominal cavity (causes swelling)

Transudates v. Exudates

Exudates
- edema due to increased vascular permeability

Transudates
- edema due to increased hydrostatic pressure or reduced intravascular proteins

4 Important Practical Factors

- increased intracapillary pressure
- decreased plasma osmotic pressure
- lymphatic obstructions
- retention salt/water

Cardiac Edema

1) decrease in renal blood flow
2) RAAS: activate hormones that cause retention of Na+ and water by kidney
3) increase intracapillary pressure & blood volume

Renal Edema - nephritic

- acute glomerulonephritis
- related to Na+ which increases water retention
- transudate (edema due to increased hydrostatic pressure or reduced intravascular proteins)

Renal Edema - nephrotic

- heavy proteinuria (protein in urine) due to leaky capillaries
- loss of albumin that exceeds livers' production
- decrease in plasma oncotic pressure

Nutritional Edema

- prolonged starvation = loss of subcutaneous fat
- surrounding tissue becomes looser -> less tissue tension
- space gets filled with fluid -> edema

Chronic Liver Disease Edema

- edema is present as ascites
- increase intracapillary pressure --> decrease albumin/plasma oncotic pressure --> increase hepatic lymph

Pulmonary Edema: Increased intracapillary pressure

- IV overload
- increase in altitude
- severe anemia
- renal failure

Pulmonary Edema: increased capillary permeability

- ARDS
- aspiration
-DIC
- pneumonia: infectious or chemical
- bacteremia
- severe trauma

Local Edema: 3 Types

1) increased intracapillary pressure
- occlusive venous thrombosis
2) increased local vascular permeability
- inflammation, type I hypersensitivity (allergy)
3) lymphedemia
- obstruction of lymph flow due to surgery, inflammation, or filariasis
- worms live in lymph system and act as blockages