What are the mechanical barriers of natural (innate) immuntiy?
- Ciliated cells in nose and bronchus
What are natural killer (NK) cells?
Special T lymphocytes
What are some protective proteins involved in natural (innate) immunity?
Lysozyme (tears, nasal, intestinal secretions)
What is the form of immunity that is obtained during life?
What are the characteristics of immunocompetence?
- Distinguish self from non-self
- Generate an immunologic memory
- Mount an integrated reaction of various cells
What is a chemical substance that can induce a specific immune response?
Antigen (bacteria/viruses, etc)
What WBCs are slightly larger than RBCs with a large nucleus and small amount of cytoplasm?
What are the primary lymphoid tissues that produce lymphocytes?
- Fetal liver/bone marrow: B lymphs
- Thymus: T lymphs
What are the secondary lymphoid tissues that have mature lymphocytes?
- Lymph nodes (tonsils, adenoids)
- Peyer's patches in small bowel
Where do T-lymphocytes first arise and where do they mature?
- Pre-T cells are from bone marrow.
- They are then transported to the thymus where they mature and become active in the medulla, then move on to the blood stream.
- **Thymus becomes small in adults.
What percentage of circulating lymphocytes are made up of T-lymphocytes?
What is different about T cells as compared to B cells in terms of recognizing antigen?
- T cells do not recognize free-floating antigens.
- However T cell receptors are vital for antigen recognition.
What are the types of T cells in the body?
- Natural killer (NK) cell: lack TCR on surface, do not need stimulation or prior exposure to work, recognize virally infected cells/some cancer cells, destroy cell membranes
- CD4: T-helper cells
- CD8: T suppressor/cytotoxic cells
What do CD4+ T cells (helper cells) do?
- Help B-lymphs produce antibodies
- May be activated to secrete cytokines
- Activates eosinophils
What to CD+ T cells (suppressor/cytotoxic) do?
- Suppress unwanted antibody production
- Mediate killing of cells recognized as foreign (cells infected by viruses, tumor cells)
What are the different cytokines (proteins for intercellular communication) and what are their functions?
- Interleukins: promote T and B lymphs and others
- TNF: kills tumor cells and other pro-inflammatory actions
- Interferon γ: against viral, bacterial and tumor cells
- Growth factors: produced by nucleated cells esp endothelial and epithelial cells and macrophages, interact w/ receptors on target immune cells
What proteins are produced by plasma cells that react with antigens; act as antibodies?
What percentage of circulating lymphocytes are made up of B lymphocytes?
Where do B lymphocytes tend to congregate? What can they differentiate to?
- Germinal centers of lymph nodes and lymphoid follicles of the spleen.
- Plasma cells (full differentiated B cells stimulated by antigens)
What part of immunoglobulins is the same for all classes? Which part differentiates the classes of immunoglobulins?
- Light chains are all the same (Kappa or Lambda).
- Heavy chains are immunoglobulin class specific.
What are the classes of immunoglobulins and their characteristics?
- IgG: small Ig, crosses placenta, facilitates opsonization, passive immunity after birth
- IgM: largest Ig, neutralize microorganisms with five complement binding sites, 1st to form after immunization/infection, natural Ab to ABO Ag
- IgA: mucosal secretions (Achoo), breast milk, intestine
- IgE: secreted by sensitized plasma cells in tissues and attached to mast cells, mediates allergic reactions (hay fever or asthma)
- IgD: membrane-bound immunoglobulin found exclusively on B cells
What type of reaction is an abnormal immune response to exogenous antigens or endogenous auto-antigens?
What are the types of hypersensitivity reactions?
- Type I: anaphylactic type reaction
- Type II: cytotoxic antibody mediated reaction
- Type III: immune complex mediated reaction
- Type IV: cell mediated, delayed type reaction
Which type of hypersensitivity is mediated by IgE and mast cells or basophils?
Type I Hypersensitivity (anaphylactic)
Explain the process of a type I hypersensitivity reaction.
- Ag stimulate B lymphs which differentiate into plasma cells that produce IgE.
- IgE Ab sensitize mast cells (tissue) and basophils (plasma).
- Re-exposure to the Ag leads to formation of Ag-Ab complexes on mast cells.
- Mast cells release inflammatory mediators (histamine-vascular permeability-edema) promoting accumulation of inflammatory cells (esp EOSINOPHILS).
What is the range of clinical examples for a Type I hypersensitivity reaction?
Hay fever to anaphylaxis.
A life-threatening, severe, systemic response to an allergen to which the body has prior exposure.
What are the clinical symptoms of anaphylactic shock?
- Choking due to laryngeal edema
- Wheezing, SOB from bronchospasm
- Pulmonary edema & circulatory collapse from hypotension (due to vasodilation)
What condition is often considered a Type I hypersensitivity reaction in children? What is another example of a Type I reaction other than anaphylaxis?
- Atopic dermatitis (not the same as contact dermatitis)
Which type of hypersensitivity reaction occurs due to antibodies binding to antigens IN or ON cells or tissue components such as basement membrane?
Type II Hypersensitivity (cytotoxic antibody-mediated)
Explain the process of a type II hypersensitivity reaction.
- IgG or IgM form Ag-Ab complexes that activate the complement system leading to formation of the membrane attack complex (MAC), which is a major cause of cell lysis (cytotoxicity).
- Basement membrane of endothelial cells can be damaged and cause fluid leaks.
What generally are the causes of a type II hypersensitivity reaction?
- Intrinsic causes: auto-immune
- Extrinsic causes: may be drug, virus, chemicals
What diseases are examples of cytotoxic antibody-mediated (type II) reactions?
- Graves Disease
- Goodpasture's syndrome
- Myasthenia Gravis
- Auto-immune hemolytic anemia
What is Grave's disease? How is the body affected?
- Form of hyperthyroidism (thyrotoxicosis)
- Auto-antibodies bind to TSH receptors on surface of thyroid follicular cells which stimulate thyroid cells to over produce thyroid hormone.
What causes Goodpasture's Syndrome?
- Auto-antibodies attach to a collagen component in the basement membranes of lung and kidney cells, resulting in an immune response (damaging glomeruli and lungs).
- Results in destruction of renal and lung tissue.
What is myasthenia gravis? How does it affect the body?
- Muscle disease marked by severe muscle weakness.
- Auto-antibodies attach to Ach receptors on surface of striated muscle cells, blocking them, therefore not allowing Ach to stimulate the receptors.
What causes auto-immune hemolytic anemia? What other disorders can this be associated with?
- Auto-antibodies against RBC antigens (causes clumping, destruction of RBCs, fragments of RBCs collect in the spleen causing splenomegaly).
- May be associated with other auto-immune disorders like systemic lupus erythmatosus, and drugs (methyldopa).
Which type of hypersensitivity reaction is mediated by immune complexes formed by Ag and appropriate Ab?
Type III Hypersensitivity (immune complex-mediated reaction)
Where can type III hypersensitivity reactions occur in the body?
- Systemic: these reactions occur when soluble immune complexes form in circulation then deposit in/on structures and initiate complement
- Local: these reactions occur when immun complexes form in the tissues
How do type III hypersensitivity reactions affect the body?
Complement recruits neutrophils and macrophages which cause acute inflammation and cell damage.
Explain the process of type III hypersensitivity reactions.
Immune complexes are filtered through to basement membranes where they become trapped in semi-permeable membranes and activate complement system.
What are some examples of Type III Reactions?
- Systemic lupus erythematosus (SLE)
- Post-streptococcal glomerulonephritis
- Polyarteritis nodosa (small & medium sized arteries become swollen and damaged)
What disease is an auto-immune disease of unknown origin, causes circulating immune complexes formed by various auto-antigens and antibodies, and results in immune complex deposition in tissues (mainly kidney, joints, and skin)?
Systemic lupus erythematosus (SLE)
Describe what happens when someone is sensitized to streptococcal antigens during acute infection and produce antibodies, causing post-streptococcal glomerulonephritis.
- Ag-Ab complexes are deposited in basement membrane of renal glomeruli causing a complement-mediated inflammatory response, affecting the renal glomeruli.
- Symptoms include decreased urine output and edema 2-4 wks after infection.
Which hypersensitivity reaction occurs without the involvement of antibodies, instead mediated by specifically sensitized T-lymphs and macrophages and requires a previous exposure to something such as poison ivy?
Type IV Hypersensitivity (cell-mediated/delayed-type reaction)
Describe the process of type IV hypersensitivity reactions.
- Reaction is mediated by complex antigens taken up by macrophages that present them to T-lymphs which then produce cytokines (esp interferon γ) primed and activated against the antigen.
- Under influence of cytokines, macrophages become epithelioid cells which promote formation of granulomas (epithelioid cells, giant cells, lymphocytes) such as in TB, sarcoidosis, leprosy.
Which cells are are mainly involved in type IV hypersensitivity reactions?
Langerhans (dendritic) cells of the skin which take up and process antigens (APCs).
What is the most common clinical form of a type IV hypersensitivity reaction? What are examples of response to other complex antigens?
- Contact dermatitis: ie., poison ivy (most common, no granulomas) resulting in wheal formation/vesicles.
- Others include: TB (skin test), Mycobacterium leprae, and fungi (granulomas).
What are the signs of sarcoidosis?
- Granulomas in lungs
- Enlarged lymph nodes (neck, axilla, chest)
- Skin lesions
What are the signs/symptoms of leprosy?
- Starts with hypo-pigmented skin lesion (maybe without sensation).
- Later form nodules under the skin.
- May eventually cause destruction of peripheral parts (loss of fingers, toes, nose, etc).
- **those with good immunity not susceptible after brief exposure**
What are the types of tissue or organ grafts?
- No antigenicity (shouldn't be rejected): autograft (from patient to self), isograft (identical twin to twin)
- Homograft (allograft): person to person (recipient requires immuno-suppression)
- Xenograft: animal to person; best for avascular tissues (porcine heart valve)
What types of cells are used to test donor/recipient compatibility? What antigens are of importance when testing for compatibility?
- Histo-compatibility antigens (must be same as organ cells).
- Human leukocyte antigen (HLA) haplotype (HLA-A, B, C, D, DR)/ siblings have 1:4 chance for haplotypes to be the same.
What mediates the rejection of a graft?
- Early: antibodies causing damage blood vessels
- Later: delayed cellular immunity causing tissue infiltrates of T & B lymphs and macrophages
What are some immuno-suppressive medications given to transplantation patients?
- Cyclosporines: inhibit IL 2, impair T cell response (nephrotoxic)
- Monoclonal antibodies (names end in mab): inhibit IL 2
What happens in a graft vs host reaction?
- Donor's lymphs attack host tissues.
- Involves GI tract, skin, liver.
Which blood group can donate RBCs to every other type? Who can this blood type donate serum to?
- Group O
- Plasma donor only for O (serum contains Anti-A and Anti-B antibodies)
Which blood group can donate RBCs to only the same blood group? Who can this blood group donate serum to?
- Group AB (universal recipient)
- Universal plasma donor (serum has no A or B antibodies)
Which natural blood antigen does NOT have a corresponding natural antigen?
Rh antigens (D)
What is time frame for preventing an Rh negative mother from becoming sensitized to the D antigen after given birth to an Rh pos baby? What is given and how does it work?
- Within 12 hours of delivering.
- Give Anti-D immunoglobulin (RhoGam) to mother.
- RhoGam destroys the few fetal RBCs reaching the mother's circulation to prevent her from forming Anti-D antibodies.
How long does a blood typing take? Crossmatch? When is a type and screen done?
- Few minutes
- An hour
- Need for transfusion probably low, patient blood is tested but not crossmatched until there is a request for blood, which should be available quickly.
What are the signs of a "minor" allergic reaction to a blood transfusion?
- **give diphenyhydramine, methylprednisolone, ephinephrine/can be reduced by using leuko-reduced RBCs**
What are the signs of a blood transfusion reaction due to ABO mismatch?
- Back pain
- Renal failure
What is the initial management of transfusion reaction due to ABO mismatch?
- STOP the transfusion!
- Examine urine & serum for Hgb
- Give IV fluids to main urine output.
- Give IV bicarb to "alkalinize" urine, allowing less precipitation of Hgb in kidneys.
- Send patient urine, blood and donor blood unit to the lab.
What is the "lethal triad" that blood transfusion can contribute to?
- Hypothermia (cold banked blood): warm whole blood is best (rarely available), warm RBC unit before infusing
- Metabolic acidosis, hyperkalemia (hemolyzed banked blood)
- Coagulopathy: dilution of coag factors/platelets (give FFP to correct deficiency in actively bleeding patient)
What are auto-immune disorders? What are the two forms and the characteristics of auto-immune disorders?
- Immune system cells lose ability to distinguish "self" from "non-self".
- Two forms are systemic (multi-organ), and organ-specific (limited to single organ) disease.
- Characteristics include existence of auto-antibodies, evidence that immune mechanisms are causing pathologic lesions.
What are some examples of systemic and organ specific auto-immune disorders?
- Systemic: systemic lupus erythematosus (SLE)
- Organ specific: salivary glands (Sjogren's)
Which gender and ethnicity does systemic lupus effect more? What is the age group typically affected by SLE?
- Affects females more than males (10:1)
- Increased incidence in African-American, Latino and Asian populations.
- Typically age onset 20-40
- **may be related to a virus**
What are the "eleven criteria" for identifying systemic lupus erythematosus?
- Malar rash: "butterfly" across cheeks and nose
- Discoid rash: raised red patches
- Mouth/nose ulcers: usually painless
- Arthritis (nonerosive): >/= 2 joints with tenderness, swelling or effusion
- Serositis: cardiac (pericarditis)/ lungs (pleuritis)
- Neurologic disorder: HA, seizure, psychosis, cognitive dysfunction
- Renal disease: (>50% of pts) proteinuria and/or glomerular disease (cellular casts)
- Hemtologic: hemolytic anemia, leukopenia, thrombocytopenia
- Immunologic disorder: Ab to double stranded DNA, Ab to cardiolipin
- Antinuclear antibodies (ANA): a postive test in the absence of drugs is known to induce it
- **3/11 symptoms=probable dx, 4/11=definite
How are ANA detected? Are ANAs specific only to SLE?
- No other autoimmune diseases may have ANAs
What autoimmune disease is described as inflammatory disease mediated by Ag-Ab complexes typically involving small to medium-sized arteries?
What is the antigen that causes polyarteritis nodosa? What are the early and chronic stages?
- Antigen causing reaction usually unknown but may be linked to chronic hepatitis B.
- Early stage: fibrinoid necrosis and acute inflammation of affected vessels
- Chronic stage: destruction of vessel wall and formation of microaneurysms
What is the "CREST syndrome" used to describe limited systemic sclerosis/scleroderma (systemic autoimmune disease of skin)? What is the sign of diffuse systemic sclerosis/scleroderma?
- Raynaud's phenomenon
- Esophageal dysfunction
- Diffuse systemic sclerosis/scleroderma: rapidly progressing involving skin and internal organs
What is an autoimmune disease in which auto-antibodies affect salivary glands and tear glands? What are the clinical symptoms and what are some other organs that may be involved?
- Sjogren's Syndrome
- Clinical symptoms: dry eyes, lack of saliva
- May also involve: lungs, GI tract, thyroid, parotid, kidney
What are possible causes for immune compromise?
- Bone marrow dysfunction: congenital (primary), immuno-suppression by chemo/steroids
What are the characteristics of immune compromise? What is the more common cause of immune compromise?
- Lymphopenia: low lymph count in peripheral blood (causes reduced resistance to infections)
- Acquired (secondary) immune compromise is more common than congenital (primary).
What are clinical examples of primary immunodeficiency disease caused by congenital disorders affecting differentiation and maturation of the T & B lymphocytes?
- Isolated deficiency of IgA (most common); due to a block in terminal differentiation of B cells to IgA
- Severe combined immunodeficiency: defect in lymphoid stem cells (pts lack T & B cells)
- DiGeorge syndrome: deficiency of T cells due to lack of thymus development
What is the ratio of CD4 to CD8 in someone with AIDS as compared to the normal ratio of 2:1? What effect does this have on the patient?
- With AIDS ratio is <1
- Impairs patient's natural immunity (virus uses host cell to produce viral RNA, can exist for years without harming cells).
What is the cause of AIDS? What kind of agent it is and what is the mechanism of infection?
Human immunodeficiency virus (HIV): retrovirus via reverse transcriptase, RNA virus is replicated in host cell (esp T-lymphs) to produce DNA from viral RNA; virus fuses with cell membrane and destroys it (cell death)
How many people are infected worldwide? How many died? Who is affected in the US and worldwide?
- 59 million
- 20 million died (usually from opportunistic infection)
- In US 64% new cases from men how have sex with men.
- Worldwide affects mostly heterosexuals (prevalence increased with other STDs and uncircumcised men, only a few HCP have died of AIDS acquired in the professional setting).
What are some of the opportunistic infections that can affect someone with AIDS?
- CMV (eyes)
- Candida (mouth, esophagus)
- Cryptococcus (meningitis)
- TB (lungs, GI tract)
- Herpes simplex (skin)
- Tumors (Kaposi sarcoma-red/brown/purple patches or nodules on skin and mucosa caused by HSV; lymphoma-lymph nodes, skin, gut, brain)
What is the treatment for AIDS aimed at?
- Inhibiting viral replication.
- Monitoring progression with CD4+ T-cell counts (time from intro of virus to sero-conversion is about 2-3 weeks but can take up to 10 years; symptoms happen when CD4 <200).