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NU 231 Pathophysiology Immunity Topics: 13 - Immune Response 14 - Inflammation and Tissue Repair 15 - Alterations in Immune Response IMMUNE RESPONSE TWO MAJOR DIVISIONS OF THE IMMUNE SYSTEM Non-Specific Immune System Also called INNATE OR NATURAL IMMUNITY First line of defense. Components of non-specific immunity Physical Barriers Skin, mucous membranes Chemical Barriers Antibacterial substances inhibit growth Fatty acid Lysozyme Cellular Barriers Neutrophils and macrophages (major phagocytic cells) Natural Killer Cells (NKC) Physiologic Barriers Fever Low pH (skin, stomach, vagina inhibit growth) Complement System Produces inflammatory response Promotes phagocytosis and cell lysis Characteristics o No specificity; broad spectrum - acts on many organisms, unable to differentiate between organisms o No memory response; thus, no lasting immunity o Able to distinguish self from non-self Specific Immune System Also called ACQUIRED OR ADAPTIVE IMMUNITY 2 nd^ Line of Defense, acquired through previous exposure Key Players = LYMPHOCYTES (B & T Lymphocytes) Characteristics o Specificity - Have specific cell membrane receptors that target specific antigens o Memory Response - Remembers exposure to antigen and quickly responds on subsequent exposure o Recognition of Self from Non-Self - Prevents reaction against own tissue (Self- Antigens)
IMMUNE STRCTURES
Central Immune Structures Bone Marrow o Produces B & T Lymphocytes from precursor cells in bone marrow o B cells mature in bone marrow o B-Cells provide humoral or antibody-mediated immunity Thymus: o T-Cells mature in thymus o Made in the bone marrow o T-Cells provide cell-mediated immunity Peripheral Immune Structures Lymph Nodes Tonsils Spleen Appendix Peyer’s Patches in intestines Mucosa-associated lymphoid tissue in Respiratory, GI, & GU Tracts Function o Traps and processes the antigen o Promotes interaction with mature immune cells ANTIGENS / IMMUNOGENS Antigens / Immunogens Foreign substance that can stimulate the production of antibodies (immunoglobulins): Also a substance that can INITIATE an immune response Foreign Antigens o Pathogens (bacteria, viruses, protozoa, fungi, parasites) o Plant Pollen o Poison Ivy Resin o Transplanted Organ
o Incompatible Blood Transfusion
MHC:
Major Histocompatibility Complex MHC is cluster of genes located on chromosome 6 Codes for HLA (Human Leukocyte Antigens) o First detected on WBC because of their role in organ transplants o HLA found on surface of nearly every cell in the body o “Self Antigens” o ONLY identical twins have the same HLA, that’s why organs are often rejected o Allows immune system to distinguish “self from non-self”
Granulocytes NEUTROPHILS o Primary phagocytic cell o Also known as ▪ PMN = Polymorphonuclear Neutrophil ▪ Segs = Segmented Neutrophil ▪ Bands or Stabs = Immature Neutrophils o Increase during bacterial infection ▪ Leukocytosis = ↑ WBC > 10,000 (15,000 to 20,000) ▪ Shift to the left = Increase in immature neutrophils (Stabs/Bands) o First to arrive at injury site - within 90 minutes o Lifespan = 4-5 days BASOPHILS o Contains histamine and other chemical mediators EOSINPHILS
o Increases during an allergic reaction or parasitic infection
Agranulocytes MONOCYTES / MACROPHAGES o Primary phagocytic cell o Monocytes mature into macrophages as it migrates to injured site o Arrives within 24 hours o Engulfs and destroys foreign substance
o Found in large quantities in spleen, lymph nodes, tonsils, Liver (Kupffer Cells),
Skin (Langerhans Cells), Lung (alveolar macrophage), Brain (Microglial Cells) NATURAL KILLER CELLS (NKC) o Important in Non-Specific Immunity o Kills cancer cells and virus infected cells o Does not have ability to distinguish one antigen from another. NK cells don’t care what kind of antigen it is. o Kills cancer cells and virus infected cell. B-LYMPHOCYTES o Responsible for specific immune response o Formed from stem cells in bone marrow; mature in the bone marrow o Less than 1% enter circulation o Acquire specific membrane receptor for a specific antigen o Provide HUMORAL IMMUNITY, or antibody mediated immunity o When B-Lymphocytes encounter complementary antigen, they differentiate into: ▪ Plasma Cells - Produce antibodies ▪ Memory Cells - Remember exposure to antigen
Five Classes of Antibodies / Immunoglobulins IgA Found in body secretions: Tears, Saliva, Resp., GI, Vagina, Prostate, and Colostrum (1st^ milk of nursing mothers) Prevents attachment of viruses and bacteria to epithelial cells Considered primary defense against local infections in mucosal tissue IgD Found primarily on the cell membranes of B-Lymphocytes Serves as antigen-receptor for initiating differentiation of B-Cells IgE Involved in inflammation and allergic responses & parasitic infections IgG Most abundant immunoglobulin Protects against bacteria, viruses, toxins in body fluids Activates complement system Crosses placenta - transfers immunity from mother to fetus o Provides PASSIVE IMMUNITY - Short-lived (3-6 months) o Largest amount crosses placenta during last weeks of pregnancy Synthesized during SECONDARY RESPONSE , which suggests past infection IgM Largest immunoglobulin Synthesized during PRIMARY RESPONSE , which suggests current infection First antibody made by newborn o Presence of IgM rather than maternally transferred IgG is indicative of newborn infection PRIMARY RESPONSE Occurs when antigen first introduced into body Lag Time - takes a few days before antibodies detected in blood IgM Predominant antibody (suggests current infection) SECONDARY RESPONSE Occurs on 2nd^ exposure to same antigen No Lag Time - Rapid rise in antibody produced Memory Cells remember past exposure to antigen IgG predominant antibody (suggests past infection)
INFLAMMATION
Complex biological response of tissue to harmful agents Causative Agents: o Microbial Agent: Bacterial, Virus, Fungi, Protozoa o Non-microbial Agent: Physical injury, surgery, burns, chemical agents, etc. Named by adding suffix “itis” to the affected organ or system o Tonsillitis o Appendicitis o Hepatitis Inflammation is a prerequisite to healing o Without inflammation, wounds would not heal, minor infections would become overwhelming. o However, some forms of inflammation (e.g. Rheumatoid Arthritis) are not beneficial Purpose of Inflammation o Destroys & neutralizes harmful agents o Limits spread of tissue damage o Prepares damaged tissue for repair Types of Inflammation: Acute and Chronic Inflammation ACUTE INFLAMMATION Initial response of body to harmful stimuli Rapid Onset Lasts < 2 weeks Local signs and symptoms o Redness o Heat/Warmth o Swelling o Pain o Impaired Function Systemic signs and symptoms o Fever o Enlarged lymph nodes o Elevated WBC Count o Elevated Erythrocyte Sedimentation Rate [ESR], C-Reactive Protein [CRP] o Loss of Appetite o Increased Sleep Three Responses:
○ Vascular Response, Cellular Response and Inflammatory Mediators
Vascular Response Characterized by small changes in blood vessels at site of injury Begins almost immediately after injury Lasts a few seconds to minutes Transient vasoconstriction Vasodilation = Increases blood flow increases warmth & redness Capillary Permeability
○ Fluids move out of capillary and into interstitial space
○ Leads to swelling irritates nerves Pain Loss of Function
○ Fluid dilutes toxic agent & brings chemotactic substances to area
Cellular Response Movement of WBC to injured site Steps: o Margination & Adhesion o Emigration aka: diapedisis o Chemotaxis o Phagocytosis Inflammatory Mediators Injury / pathogen causes the inflammation but inflammatory mediators enhance the inflammatory response - redness, heat, swelling, pain, loss of function Inflammatory Mediators include the following Histamine Sources: o Mast cells (major source) o Basophils & Platelets Released in response to allergic & anaphylactic reaction Action o Vasodilation Redness, warmth o Capillary Permeability Swelling Meds: Antihistamines o Claritin, Clarinex, Zyrtec, Allegra o Benadryl, Chlor-Trimeton
Complement System Primary mediator of both nonspecific and specific immune response Group of proteins normally present in circulation as inactive precursors Action o Produces inflammation o Promotes phagocytosis and cell lysis Activated by: o Viruses, bacteria, and immune complexes Cytokines Synthesized by primarily by T-Helper Cells and Macrophages Function o Cell-to-cell communication o Activates B and T cells o Stimulates proliferation of CD8+ and NKC o Enhances macrophage activity Four Types of Cytokines o Interuleukins (IL 1 - 18) Activates T lymphocytes Promotes growth and differentiation of B-Cells Synthesis of other cytokines Induces systemic fever o Interferons (α & β)) Exerts antiviral activity Produced by host cell invaded by virus Protects uninfected cells from viral invasion $$$$ and has big time side effects Generally used for HepC (chronic) o Tumor Necrosis Factor (TNF) Produces inflammation & fever Activates phagocytosis Kills through apoptosis o Colony Stimulating Factor (CSF)
Promotes growth and maturation of neutrophils,
eosinophils, macrophages
ACUTE INFLAMMATORY EXUDATE
Exudate composed of fluids and plasma proteins that leak out of blood vessel, which combines with neutrophils and cellular debris from phagocytes Four types of exudates Fluid that occurs as result of infection (oozing of infected wound) Serous Thin, watery exudate with low protein count Example: Skin Blister, Genital Herpes Purulent Contains pus - consists of neutrophils, bacteria, and fluid Infection by pyogenic bacteria such as staphylococci is characteristic of this kind of exudate Example: Abscess - localized collection of pus enclosed by surrounding tissue Hemorrhagic Injury ruptures blood vessel Exudate looks bloody Fibrinous Commonly seen in serous cavities Forms a thick, stringy exudate Has high protein content and increased fibrinogen Example: Bowel Adhesions, fibrinous pericarditis, CHRONIC INFLAMMATION Prolonged inflammation Lasts > 2 weeks (weeks, months, years) Caused by:
○ Persistent acute inflammation that is resistant to phagocytosis and other inflammatory
mechanisms
● Examples:
○ Foreign bodies (silica, asbestos, surgical suture, splinters, dirt)
○ Low-Virulence Pathogens (Tubercle Bacillus [TB], Treponema Pallidum [Syphilis])
○ Autoimmune reaction (rheumatoid arthritis)
Major cells that are involved: Macrophages and Lymphocytes
● Proliferation of fibroblasts (instead of exudates) increases risk of scarring & deformity
ALTERED IMMUNITY (Allergic & Hypersensitivity Disorders & HIV/AIDS) ALLERGIC OR HYPERSENSITIVITY DISORDERS Refers to excessive or inappropriate activation of the immune system Four Types o Type I - IgE Mediate Hypersensitivity o Type II - Antibody-Mediated (Cytotoxic) Hypersensitivity I, II, and III all have Ab involvement o Type III - Immune Complex Mediated Hypersensitivity o Type IV - Cell Mediated (Delayed Hypersensitivity Disorders): NO Ab involvement Type I: IgE Mediated Hypersensitivity Antibody = IgE Antigen = Allergen (Pollens, dust mites, mold, animal dander, drugs, food, insect bites, etc.) Mast Cells o Located in skin & mucosa o Contains granules of inflammatory mediators (e.g. histamine) Stage I: Initial Encounter o IgE Antibody attaches to mast cell o Mast cell becomes “sensitized” Stage II: Subsequent Exposure o Allergen binds to IgE antibody on “sensitized” mast cell o Triggers release of histamine & other inflammatory mediators ▪ Vasodilation ▪ Vascular permeability ▪ Bronchoconstriction Type 1: IgE Mediated Disorders o Systemic Reaction ▪ Anaphylactic Reaction o Local Reaction (atopic = genetic predisposition) ▪ Allergic Rhinitis (hay fever) ▪ Atopic Dermatitis ▪ Food Allergies ▪ Bronchial Asthma
Systemic Reaction ANAPHYLACTIC REACTION o Triggered by: Drugs, Insect bites/stings, Foods o Life threatening o Characterized by wide-spread vasodilation o Occurs in persons who have previously been sensitized o May be accompanied by Urticaria and with or w/o Angioedema
Urticaria = Hives
Angioedema = Involves deeper skin layers; presents with
swelling of soft tissue of head and neck including eyes, lips, tongue and palate o Signs & Symptoms of Anaphylaxis ▪ Skin – flushes and becomes warm; hives itching ▪ Throat – Throat & tongue swell airway obstruction ▪ Respiratory – Chest tightness, wheezing, SOB ▪ CV – Hypotension (profound vasodilation circulatory failure); tachycardia Local Reaction ALLERGIC RHINITIS o Seasonal (Pollens) or Perennial (Dust mites, animal dander, molds, cockroaches) o Signs and Symptoms ▪ Fatigue / Malaise ▪ Red, itchy eyes ▪ Nasal congestion ▪ Runny nose ▪ Sneezing ▪ Itchy ears, palate FOOD ALLERGIES o Milk, Eggs, Fish/Shellfish, Wheat, Soybeans, Nuts (peanuts, walnuts, pecans, almonds, cashews) o Nuts most responsible for anaphylactic reaction
Type IV Cell-Mediated Disorder Also called delayed hypersensitivity disorder Takes about 2-3 days to develop Clinical Examples: o TB skin test o Allergic Contact Dermatitis Poison Ivy/Oak Latex Allergy (can be type I or type IV) Nickel (jewelry) o Transplant Rejection TB Skin Test Used to screen for TB; Use PPD – Purified Protein Derivative Inject PPD into forearm (intradermal injection) & read it 48-72 hrs later (+) PPD = Redness and induration at site of injection o Occurs in person who has been previously exposed to TB and has “sensitized” T Cells o Takes 2-4 weeks after TB exposure to produce “sensitized” T lymphocytes Poison Ivy/ Oak T cells interact with antigen (plant sap / plant resin) Blisters erupt in 12-24 hours after exposure Rash occurs only where skin comes in contact with plant sap Need more than 1 exposure to produce “sensitized” T lymphocytes Blister fluid DOES NOT contain the allergic plant sap Latex Allergy (gloves) Allergic reaction results from latex protein coming into contact with skin, mucous membranes or internal organs Persons at high risk for sensitization include: o Frequent exposure to latex gloves
Person who has had many surgeries
Kids with spina bifida (undergo frequent examinations)
Health care workers
May cause a Type I or Type IV mediated response Type 1: IgE Mediated Hypersensitivity o Less common but more serious o Itchy, watery eyes, asthma, urticaria or ANAPHYLAXIS Type IV: Cell Mediated Response o More common, less serious o Contact dermatitis = vesicular rash o Develops 48-72 hours after contact with latex
HIV / AIDS
HIV = Human Immunodeficiency Virus AIDS = Acquired Immunodeficiency Syndrome HIV primarily infects T-Helper Cells and Macrophages (both have CD4 receptors: normal count is 500-1500; AIDS CD4 count <200) Transmission SEXUAL TRANSMISSION Vaginal Intercourse o Virus can be transmitted in either direction o However, men are 2-3x more likely to transmit to women than visa versa ▪ Semen contains more HIV than vaginal fluid ▪ Women exposed to larger qty of infectious fluid (ejaculate) ▪ Ejaculate retained in vagina longer period of time Anal Intercourse o Anal mucosa is fragile - tears easily o Most efficient means of transmission Oral Sex o Less risky than vaginal and anal sex o HIV can enter body thru lining in the mouth CONTACT WITH INFECTED BLOOD OR BLOOD PRODUCTS NEEDLE STICK INJURIES o Risk is < 1% o 99% of needle stick injuries DO NOT lead to infection o HBV risk = 30% o Prevention (universal precautions) ▪ Wear gown, gloves, protective eye shield ▪ Never recap needle ▪ Wash hand immediately NEEDLE SHARING o IV Drug Users (IVDU) sharing needles/syringes o Athletes sharing needles to inject steroids TRANSFUSION WITH INFECTED BLOOD o Risk is < 1% o Blood donations screened for HIV (started in 1985) TISSUE TRANSPLANTS o Risk is low in US - tissue is tested
Phases of HIV EARLY SIGNS & SYMPTOMS Signs & symptoms of immune deficiency but not serious enough to be defined as AIDS Signs & Symptoms o Fever, Fatigue o Candidiasis (oral, vaginal) o Seborrheic dermatitis o Cervical Dysplasia o Enlarged Lymph Nodes ( 2 locations x 3 months) o Viral Load ↑; CD4+ Count ↓ AIDS Develop life-threatening opportunistic infections & malignancies Examples: (Complete list is in textbook) CD4+ count < 200 cells / microliter of blood HIV Terminology Window Period o Time after infection but before seroconversion o HIV antibody test = NEGATIVE Seroconversion o Point at which infected person converts from a NEGATIVE TO A POSITIVE Antibody Test o Most take 3 months to seroconvert o A few may take up to 6 months to seroconvert HIV Screening Tests
ELISA TEST
o HIV Antibody Test o Initial test o Less expensive o If (+), confirm with a Western Blot o Get results in 2 weeks Western Blot Test o More expensive o More sensitive OraSure o HIV Antibody Test o Mouth Swab o Mail specimen to lab for testing; takes 2 weeks to get results o Accurate but not as accurate as blood tests
● OraQuick Advance
o HIV Antibody Test o Finger stick or mouth swab test o Results in 20-30 minutes o Very accurate Home Access HIV-1 Test o FDA approved o Finger prick o Mail specimen to lab for testing; takes about 7 days to get results o Very Accurate Other Lab Tests CD4+ Count o Normal = 500- o Used to monitor progression of disease and manage the disease Viral Load o Measures level of HIV RNA in blood o Used to manage the disease
Treatment No vaccine, no cure Several drugs available to fight infection Drugs called HAART - Highly Active Antiretroviral Therapy Use combination of drugs to stop viral replication and delay development of AIDS Prevention Avoid behaviors that put you at risk Know HIV status of sexual partner Abstain from sex Mutual monogamy Use condoms consistently Do not share needles/syringes Use universal precautions if you are a health care provider Be cautious of blood and blood products in other countries Get tested if you’ve engaged in risky behavior or received blood in another country DON’T BE COMPLACENT!!!
