Hypersensitivity

An inappropriate immune response

exaggerated against environmental antigens (allergies)

misdirected against one's own cells (autoimmunity)

directed against transplants (alloimmunity)

reactivity to an intigenthat results in a pathological immune response after reexposure

can be delayed or immediate

• rapid and severe hypersensitivity reaction that occurs minutes after reexposure to an antigen
• Itching, erythema, vomiting, abdominal cramps, diarrhea and/or breathing problems accompany anaphalaxis
• Respiratory distress, sock, and death may occur

• Type I - IgE: medited allergic (seasonal allergies)
• Type II - tissue specific (ex: Graves Disease, autoimmune hemolytic anemia)
• Type III - immune complex (antibody bound to its antigen) mediated (ex: systemic lupus, erythematosus). Can trigger complement.
• Type IV: cell mediated (ex: contact sensitivity to poison ivy or metals)

• the initial sensitivity to an allergen causes B cells to make IgE
• the IgE then binds to IgE-specific FC receptors on mast cells (which contain inflammatory mediators like histamine)
• re-exposure causes the allergen to cross-link IgE on mast cell surface
• mast cells degranulate to release histamine
• histamine binds to H1 receptors
• bronchoconstriction occurs, and permeability in microcirculation increases (edema)

• itching
• conjuntivitis
• rhinitis
• angioedema (partial swelling)
• laryngeal edema
• urticaria (spots)
• hypotension
• bronchospasm 
• dysrythmias
• gastrointestinal cramps and malabsorption

• tissue specific reaction
• antigens on the target cell binds to an antibody
• the binding causes destruction or improper function
• Sequelae to antibody binding in type II reaction can trigger:
• phagocytosis by macrophages
• complement-mediated lysis
• antibody-dependent cell-mediated cytotoxicity
• blockage of cell surface receptors

• immune complexes (antigen+antibody) depositied in healthy tissue or blood vessels
• complement cascade activated
• neutrophils recruited and destroy healthy tissue

• self-antigens stimulate T-cell differentiation into Tc and Th1 (Td-delayed) cells
• Th1 cells release cytokines
• cytokines recruit macrophages
• macrophages destroy tissue

• The body's own immune systen recognizesself-antigens as foreign because of breakdown in tolerance
• Some forms of hyper/hypothyroidism
• rhematoid arthritis
• Type I Diabetes

Systemic Lupus Erythematosus

(SLE)

• a chronic, multisystem, inflammatory disease
• one of the most common, serious, and most cmplex autoimmune disease
• There is a production of a large amount of auto-antibodies that may be against:
• nucleic acids
• RBCs
• platlets
• coagulation proteins
• Auto-antibody dound to self-antigen may deposit glomerular basement membrane or renal tubes, inducing inflammatory cascade and damaging the kidneys
• more common in females 10:1, 20-40 year age group
• genetic predisposition 
• transient lupus-like syndrome assocated with certain drugs

• Arthralgias/arthritis
• vasculitis and rash
• renal disease
• hematological diseases (ex: anemia)
• cardiovascular disease

• develops slowly with exacerbations and remissions
• difficult to diagnose. Diagnose with 4 or mroe of the following:
• rash on cheeks
• discoid rash
• photosensitivty
• ulcers in mouth and nose
• arthritis in two peripheral joints
• pluerisy/pericarditis
• renal disorder
• neirological disorder
• immunological abnormalities
• positive antinuclear antibody (ANA) test

• failure of self-defense mechanisms to function at normal capcity
• creates an increased susceptibility to infections
• Two main types:
• Primary - due to genetic anomaly
• Secondary - due to another disease, illness or condition, response to a drug (cancer, infection, aging AIDS)

• usually a result of a gene defect
• usually the gene mutations are sporatic and not inherited
• symptoms usually apear within the first 2 years of life

Sever Combined Immunodefficiency 

(SCID)

• A type of primary immunodeficiency
• defects in both T and B cells
• "Bubble Boy Disease" - highly publicized account of David Vetter who lived in a bubble
• David had an X-linked form of SCID
• genetic forms can interefere with interleukin receptor struction/function, an enzyme that makes deoxyribonucleotides, and T and B cell receptor constuction
• stem cell/boen marrow transplants are an important treatment

• Aquired deficiencies are more common than primary
• not related to primary genetic defect, but a consequence of other problems
• conditions assocated with secondary:
• pregnancy
• aging
• stress
• eating disorders
• infections
• medical treatments 
• Treatments:
• Gamma-glubulin, antibody-rich fractions from plasma of multiple donors
• Tranplantation and transfusion
• stem cells
• thymus
• immune modulators (like cytokines)
• gene therapy

• RBCs- tissue oxygenation
• WBCs- efense against microorganisms and removal of debris
• platelets - coagulatio and bleeding control

• classified at granulocytes ot agranulocytes
• granulocutes: neutrophils, basophils, and eosinophils (phagocytes)
• agranulocytes: monocytes/macrophages (phagocytes), and lymphocytes (immunocyte B and T cells)

• Uncommitted pluriptential stem cell (+erythropoietin)->
• committed proerythroblst ->
• normobalst (nucleus shrinks and is reabsorbed) ->
• reticulocye (cell elaves marrow and enters blood stream) ->
• erythrocyte (cell achieves final size and shape: hemoglobin synthesis ceases)

• the central reaction is the conversion of plasminogen to the enzyme plasmin.
• activity of the pasminogen is achieved by the extrinsic pathway intiated by the release of tissue-type plasminogen activator 1-PAI released from the enothelial cells and by the intrinsic pathway from factor XIIa and urokinase
• plasmin splits fibrin in the clot into fibron degredation products

• Hematocrit - 40-50%
• Hemoglobin - 13.5 - 18.0 g/dl
• RBC count - 4.2-6.0 x 10^6/microleters
• WBC count - 5.0-10.0 x 10^3/microleters
• platelet count - 140,000-340,000/mm^3

"Too Little"

• Reduction in the total number of circulating RBCs or a reduction in the quantity of hemoglobin
• Causes:
• impaired RBC production
• blood loss
• increased RBC destruction
• Combination of above

"Too much"

• excess of RBCs
• relative form
• absolute form
• Rare primary form of absolute (polycymia vera [PV]) - a mutation, opr change, in the body's JAK2 gene is the main cause of PV. The JAK2 gene makes a protein that is an important compnent of cytokine signaling pathways and that helps the body produce blood cells
• common secondary form
• indivuals may develop bleeding abnormalities due to "consuption" of clotting factors in clots in microcirculation
• symptoms: HA or "full feeling" in head, visial problems, diziness, weakness, high BP, and sweating
• Treatment: phlebotomy to reduce erythrocytosis & blood volume; smokers are urged to quit; and CHF and COPD are adequately treated
• w/o treatment - 50% die (thrombosis or bleeding) within 18 months of initial symptoms

• based on etiology or morphology 
• commonly based on cell size "cytic" and hemoglobin content "chromic"

• depends on the ability of the body to compensate for reduces oxygen-carrying capacity
• if mild and gradual, there may be symptoms only on exertion
• compensation involves the CV, respiratory, and hematological systems
• with less blood, fluid moves from the interstitium to the intravasular space
• "diluted" blood moves faster and more turbulently
• may lead to ventricular dysfunction, cardiac dilation, and valve insufficiency
• hypoxia may cause small vessel dilation and further increased flow
• heart pumps harder to meet oxygen demands and prevent pulmonary congestion - may lead to congestive heart failure

• hypoxia causes increased respiratory rate and depth, increased CO, and release of oxygen from hemoglobin
• if severe, individual may be short of breath, have a rapid pounding heart beat, be dizzy, and be easily fatigued
• if sudden and severe, peripheral vasoconstriction directs blood to vital organs - renin-angiotensis system becomes activated. Skin mucous membranes, lips, and nailbeds become pale (yellow if anemia is due to RBC destruction), and healing is impaired
• if due to vitamin B12 deficiency, there may be neurological symptoms
• myelin degeneration causes numbness, gaint problems, weakness, spasticity, and reflex problems
• finally, GI problems may occur due to reduced oxygen supply - abdominal pain, nausea and vomiting, and anorexia

• Treat underlying cause and symptoms
• include transfusions, diet corrections, supplemental iron, and vitamins

• Macrocytic-normochromic

• Microcytic-hypochromic

• Normocytic-normochromic

• large, abnormally-shaped RBCs with normal hemoglobin concentration
• defective DNA synthesis leads to immature cells dying early (few mature cells) and overproduction of hemoglobin with delayed division (large cells)
• Pernicious anemia
• folate-deficiency anemia

• macrocytic-normochromic
• caused by defective secretion of intrinsic factor (IF)
• IF is needed for absorption of vitamin B12
• vitamin B12 needed for nuclear maturation and DNA synthesis in RBCs
• causes include: congenital deficiencies of IF, adult-onset gastric mucosal atrophy, H. pylori, gastrectomies and gastritis
• familial clustering w/ gastric autoantibodies
• both RBCs and WBCs are affected
• number and size of erythroid cells increases
• large WBCs with unusual nuclei occur
• treatment involves vitamin B12 replacement by injection
• w/out treatment, indivuals may develop heart failure

• macrocytic-normochromic
• due to improper diet (alcoholics & malnourished at risk) ~10% of americans
• fad diets may contribute
• folate needed for RBC production and maturation
• folate needed for RNA synthesis
• treatment involves oral foalte

• small, abnormally-shaped cells with redces hemoglobin
• main types:
• iron deficiency
• sideroblastic
• thalassemia

• Microcytic-hypochromic 
• most common in the world!
• bleeding is usually the cause, but dietary factors are important in impoverished areas
• blood loss of 2-4 ml/day is sufficient to cause it
• in men, GI bleeding is most common cause
• in women, profuse menstruation and pregnancy are most common causes
• other causes: certain medicines, surgery that alters stomach acidity & intestinal transit time & absorption, insufficient iron intake, eating disorders
• symptoms onset usually gradual. Early: fatigue, SOB, pale earlobes and palms. Later: brittle, thin, spoon-shaped nails, sore, red tongue, swallowing difficulties
• treatment: eliminating blood loss, iron replacement

• Microcytic-hypochromic 
• a mitochondrial abnormality that leads to dysfunctional iron uptake by erythroblasts and defective porphyrin/heme synthesis
• may be due to congenital iron metabolism probelsm (moslt in males & are x-linked in transmission. heredity forms are rare), or drug/toxin effects
• genetic forms involve missense mutations in aminoluvelinic acid synthesis gene
• treatment may involve giving vitamin B6

• Microcytic-hypochomatic
• due to congenital defect in globin synthesis

• aplastic - erythropoiesis is insufficient
• posthemorrhagic
• hemolytic-premature destruction
• sickle-cell - congenital abnormal hemoglobin synthesis causes abnormally-shaped RBCs, which are susceptible to damage; sickle cells may clog and obstruct the capillary beds, leading to pain and organ damage
• anemia of chronic inflammation - increased demand

• myeloproliferative disease that causes erythrocytosis
• involves RBC precursors in the marrow
• pluripotent stem cell involvement is suggested by increased numbers of platelets and granulocytes

• essentially a physological response to hypoxia
• seen in those living at high altitudes (10,000 ft), those w/ congestive heart failure (CHF), and chronic obstructive pulmonary disease (COPD)

• due to increased blood volume and viscosity, and clogging of the microcirculation
• plethora - ruddy, red color of face, hands, feet, ears, and mucous membranes
• retinal and sublingual vein engorgement
• splenomegaly and hepatomegaly
• clinical manifestions due to vascular problems: angina, calf pain due to walking-induced spasm, thrombotic disease, cerebral insufficiency

• caused by the viral disease HIV
• HIV depletes body's Th cells
• incidence of HIV/AIds is worldwide (5 million/year). In the U.S. (~31,000/year. 400,000 currently living w/ AIDS)
• HIV-1
• cause if HIV in Western Hemisphere and Europe
• HIV-2
• cause of HIV in Africa and Southeast Asia
• Effective antiviral therapies have made AIDS a chronic disease
• Epidemiology
• blood-born pathogen
• increasing faster in women than men

RNA Virus (retrovirus):

• stores genetic material on single-stranded RNA rather than usual double stranded DN
  
• Carries an enzyme reverse transcriptase that creates a double-stranded DNA versian of the virus
• new DNA becomes part of the cell's genetic material and accelerates apoptosis

• gp120 protein binds to CD4 molecule found primarily on the surface of Th cells
• CD4+Th cells typically 800-1000 cells/mm^3, reverses CD4:CD8 ration
• co-receptors CXCR4 and CCR5 strains can be selective for these receptors- influences the tropism of teh target cells
  

• serologically negative, serologically positive but asymptotic, early stages of HIV or AIDS
• window period
• Th cells <200 cells/mm^3
• Diagnosis of AIDS is made in association w/ various clinical condition
• atypical or opportunistic infections and cancer

• Early:
• lasts about 2 weeks
• HAs, fever, flu-like symptoms
• high level of virus in blood
• Middle:
  
• lasts months to years
• few symptoms
• virus dormant in host DNA
• few virus in blood but many Abs. Basis of testing.
• continuous infection, death, and replacement of CD4 +Th cells likely by own Tc (CD8+ cells)
• Late
  
• rapid decline in CD4 + Th cells
• in <400/cubic ml (normal 1000) start treatment
• patient is week, oppurtunistic infections begin (herpes, varicella, mycobacterium(Tb), fungo, Pneumocystic)

• When CD4+ <200/cubic ml:
• lymphoma
• cancer (kaposi sarcoma)
• often fatal within a year

• HAART (highly active antiretroviral therapy)
• 3 or more drugs: usually 2 that target reverse transcrptase (fools DNA into incorporatinf it into new strand, then halts DNA synthesis), and 1 that targets viral protease (can't cleave apart precursor proteins so can't make new viral proteins)
• NOT a cure, just slows progression
  
• expensive: $7000 to $10,000 per year
• many unpleasant S/Es
• prior to HAART those infected lived only a few years, now is a chronic disease
• one person may have been cured

• no current vaccines, but progress is being made
• reduce risk behaviors

• fusion inhibitors
• interferes w/ fusion of HIV and CD4+ cells
• integrase inhibitors
  
• worked in monekys to slow disease progression; have undergone clinical trials
• entrance inhivitors (co-receptor binding inhibition)
• uses monoclonal antibodies to inhibit binding to co-receptors

• A person experiences stress when a demand exceeds a person's coping abilities, resulting in reactions such as disturbances of cognition, emotion, and behavior that can adversely affect well0being

• worked to discover new sex hormone
• injected ovarian extracts into rats
• witnessed:
• enlargement of adrenal cortex
• thymic atrophy
• development of bleeding ulcers in the stomach and duodenal lining
• He witnessed these changed w/ many agents. He called these stimuli "stressors"

General Adaptation Syndrome

(GAS)

• Selye termed this general nonspecific respinse the general adaptation syndrome (GAS)
• Three Stages:
• Alarm Stage
• arousal of body defenses
• Stage of resistance or adaptation
• mobilization contributes to fight or flight
• stage of exhaustion
• progressive breakdown of compensatory mechanisms

• Alarm Stage
• Stressor triggers the hypothalamic-pituitary-adrenal (HPA) axis
• activates sympathetic nervous system
• Resistance Stage
• begins with the actions of adrenal hormones
• cortisol, epinephrine, norepinephrine
• Exhaustion Stage
• occurs only if stress continues and adaptation is not successful
• onset of disease

• Reactive reponse
• to psychologic stressors
• anticipatory response
• anticipating a disruption in homeostasis
• conditional response
• associating a stimuli with danger
• posttraumatic stress disorder (PTSD)

• anything that demands a response in order to maintain homeostasis
• noxious
• pain, cold, trauma, hunger, electric shock
• not noxious
• life events (wedding)
• excitement

• can precipitate disease
• cardiac
• can worsen existing disease
• irritable bowel syndrome
• asthma
• autoimmune diseases
• HIV progression

• interactions of consciousness, the brain and spinal cord, and the body's defense mechanisms
• corticotropin-releasing hormone (CRH) is released from the hypothalamus
• CRH also released peripherally at inflammatory sites
• immune modulation by psychosocial stressors leads directly to health outcomes

• Catecholamines
• released from chromaffin cells of the adrenal medulla
• large amounts of epinephrine; small amounts of norepinephrine
• alpha-adrenergic receptors
• alpha1 and alpha2
• Beta-adrenergic receptors
• beta1 and beta2
• mimic direct sympathetic stimulation
• Crotisol (hydrocortisone)
  
• activated by adrenocorticotropic hormone (ACTH)
• stimulates gluconeogenesis
• elevates blood glucose level
• protein anabolic effect in the liver; catabolic effect in other tissues
• lipolytic in some areas of body, lipogenic in others
• powerful anti-inflammatory or immunosuppresive agent

• Endorphines and enkephalins
• Somatotropin (Growth Hormone)
• Prolactin
• Oxytocin
• Testosterone

• Stress-induced hormones
• proteins found in the brain that have pain relieving capabilities
• in a number of conditions, individuals not only experience insensitivity to pain, but also increased feelings of excitement, positive well-being, and euphoria

Growth Hormone

(Somatotropin)

• stress-induced hormone
• produced by anterior pituitary, lymphocytes, and mononuclear phagocytic cells
• affects protein, lipid, carbohydrate metabolism, and counters the effects of insulin
• enhances immune function

• stress-induced hormone
• released from the anterior pituatary
• needed for lactation and breast development
• prolactin levels in the plasma increase as a result of stressful stimuli

• stress-induced hormone
• produced by the hypothalamus
• produced during orgasm in both sexes
• may promote reduced anxiety

• stress-induced hormone
• secreted by Leydig cells
• regulates male secondary sex characteristics and libido
• testosterone levels decrease due to stressful stimuli

• excitability changes in the limbic system and hypothalamus
• increased catecholamines, ADH, ACTH, and cortisol
• decreased testosterone, thyroxine, and other hormones
• alterations of opioid peptides
• immunodepression
• alterations in lipoproteins
• hypercoagulations of the blood
• free radical damage of cells