6. Alterations in the immune response PDF

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Alterations in the immune response...

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Lecture 6:  Inflammatory Mediators Released by Mast Cells: o Mediators:  Are made prior to degranulation  Histamine: airway constriction, dilation of small blood vessels, increased permeability of post-capillary venules, and secretion of mucus by nasal mucosa.  Serotonin - Causes vasoconstriction  Serine Proteases  Newly formed lipid mediators: thromboxane, prostaglandin D2, leukotriene C4, platelet-activating factor  Anti-inflammatory mediators: o Arachidonic acid derivatives: (lipoxins & prostaglandins D2)  Lipoxygenase pathway: gives rise to leukotrienes (highly inflammatory) and lipoxins (anti-inflammatory)  Cyclooxygenase pathway: produces prostaglandins  Lipoxins are good at changing the physiology of the inflammatory cells  Turns off neutrophils migration  Increases MP and monocytes activation o To increase repair and gets rid of neutrophils  Nonphilogenic?  Decreases in angiogenesis and fibrosis  Shut off the Leukotrienes B4 (chemoattractant) and therefore decreasing neutrophils infiltration o Fish oil is anti-inflammatory due to omega 3 fatty acids o Cytokines (double edge sword [not IL-1ra]) mitigate some of the inflammatory response  IL-1ra: Interleukin by itself is a major pro-inflammatory cytokine  If you have the receptor antagonist > binding > IL won’t be as effective  IL-4- enhances B cells activations & Th2 cells- prominent in pathology in asthma, IgE production, mucus production  IL-6: considered pro-inflammatory  Wraps up the acute phase response o Causes the liver to make proteins > liver decides to cut down inflammatory response  IL-10: essential pro inflammatory  Down regulation of MP  IL-13: essential pro inflammatory- prominent in pathology in asthma  Because it enhances mucus production and IgE production & hypertrophy of the airways  Tissue healing and repair o First Intention: minimal tissue loss, mostly no scarring & no or minimal granulation tissue formation o Second Intention: Significant tissue loss, scarring, granulation tissue formation and slow healing (for big wounds) o Figure:  First intention: small damage, clotting, neutrophils coming in mitosis of the skin. Within 24 hours you get inflammatory response. MP & fibroblasts  Second intention- larger area of damage, clotting, neutrophils, Fibrous tissue  Scar & fibrous scar  Fibrous (tissue) scar in the heart means cardiac infarction: because cardiac muscle does not regenerate o Fibrous tissues in the heart- can see if someone had a heart attack  Systemic (whole body) Effects of Inflammatory Cytokines: o Produced by macrophages & T cells which stimulate the production of Prostaglandins E2 (reason for fever) o Cytokines (early response): TNF and Interleukin 1 & 6 trigger inflammatory response  Stimulate production of Prostaglandins E2- binds directly to hypothalamus that causes fever (reset button) o Major pro-inflammatory cytokines include TNFa (Tumor necrosis factor), IL-1&6 (interleukin) and cause:

Fever & increase in WBC count  Pyrogens (Fever producing substances) can be: o Exogenous – Bacterial products (endotoxin): because they initiate the production of prostaglandins o Endogenous –Leukocyte products: TNF-a, IL-1 will induce the production of PGE2 > fever  Acute-Phase Response caused by IL6 – increased production of complements (liver) & other antibacterial proteins (liver)  Anorexia, fatigue, malaise (discomfort) and sleepiness  Pain in muscles and joints (due to the production of cytokines)  Catabolism of lipid and protein  Pain you feel when you have the flu are not due to the virus but due to the cytokines released in response o Increase in sedimentation (storing) of RBC- less Iron > anemia  Leukocytosis: notice the percentages may decrease but the number of the cells increase o Neutrophils: 70% of normal circulating WBC jumps to 85% in inflammation  12% are stabs- premature neutrophils o Lymphocytes 29% > 14% (# increases) (mostly Th0) & monocytes (2-1) % decrease and # increase 

Hypersensitivity & allergy: The body assumes an antigen (peanuts/pollen) is harmful when it isn’t normally intrinsically harmful  Pollen- irritant- harmful  Type I hypersensitivity: o Immediate response because antibodies are already there o Atopic- familial disposition  Genetic: 1 parent has allergy- 50%, if both parents- 70% o

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You must be presensitized to the antigen to have the allergy Overview: IgE binds to mast cells and leads to degranulation  Histamine, leukotrienes (Broncho-constrictors), vasoactive amines and prostaglandins from mast cells and basophils  Fun fact: you have histamine receptors in your gut

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Figure (mechanism) 1. IgM made first 2. Class switch leads to production of IgE 3. More than 1 IgE (with business ends up) need to bind to mast cells through Fc receptor 4. Cross linking system 5. Degranulation of the mast cell Initial reaction: Mast cells release histamine, vasoactive amines, lipid mediators, leukotrienes & prostaglandinsimmediate, regular allergy symptoms Later phase response: Degranulated cells keep making lipid mediators and cytokines  Deadlier & more serious than initial phase because antihistamines don’t do anything to it Examples:  Acute anaphylaxis: Difficulty getting air in and out of their airway o Can go into organ failure due to edema o Also, blood stream compromised- harder to get oxygen -> systematic shut down  Hay fever  Food allergies Organ Effects of Mast Cell Degranulation  Biogenic amines and lipid mediators may cause:  Edema and capsular leakage  Broncho-constriction: (leukotrienes are very potent Broncho-constrictors)  Intestinal hypermotility: you have histamine receptors in your gut- different, H2 receptors, but still histamine  Cytokines and lipid mediators may cause prolonged Inflammation

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 Enzymes may cause tissue remodeling- most prevalent in people with asthma  Type II hypersensitivity: o Cytotoxic reactions- most lead to the death of cells o IgG or IgM mediated & involves Complement (causes cell bursting & chemoattractant) o Sometimes requires element being attacked to be in contact with the blood o Commonly effect cellular elements and can result in:  Opsonization and phagocytosis (RBC)  Inflammation (complement and Fc receptors)  Antibody-mediated cellular dysfunction (acetylcholine) o Examples:  Hemolytic anemia  Transfusion reactions  Grave’s Disease (hypothyroidism) o Figure 1 (RBC): o IgM or IgG attack antigens on circulating cells (RBC) o RBC becomes opsonized (attack me signal)  Covered with antibody and activated complement o This may lead to Phagocytosis or lysis o Figure 2 & 3: (on the right) (All immune cells have Fc receptor) o Complement and Fc receptor mediated inflammation: 1. IgG (antibody with business end up) binds to Fc receptor on a neutrophil 2. Once this binds to an antigen, a complement is activated  Leads to chemotaxis and inflammation in the tissue the complements are sitting on o Antibody-mediated cellular dysfunction (Grave’s disease) 1. Antibody against TSH receptor (Thyroid stimulating hormone)  Leads to hyperthyroidism: stimulate the cell to make more thyroid hormone  Unusual- autoimmune disease o Myasthenia gravis: 1. Antibodies against acetylcholine receptors and will inhibit binding of acetylcholine to the nerve terminals > leads to muscular issues  Not death of cell but blockage of area and receptor  Type III Hypersensitivity (new complex reactions): o Antibodies against soluble proteins in blood  Could be foreign- immunizations  Lupus- anti your own proteins o IgG OR IgM mediated o Inappropriate use of complements- wouldn’t be able to fight any bacterial infections o Formation of antigen/antibody immune complexes- large > clots small blood vessels which leads to vascular damage o Examples: o Serum Sickness – you are making antibodies against something that is there to protect you  If you have egg allergy, don’t take flu shots  Caused by antibody produced to horse or bovine serum used in antitoxins. Aggregates of IgG activate complement  Activation of complement > inflammatory rxn o Arthus Reaction – Dermal inflammatory response, caused by reaction of antibody to antigen in skin  The problem protein had to be there because the first time you see an antigen nothing happens

2nd time seeing an antigen: locally produced antibodies causing formation of immune complexes which leads to complement activation and degranulation of mast cells  Then, Histamine receptors on blood vessels are activated > vasodilation > inflammatory response  Type IV hypersensitivity: o Cell mediated or delayed hypersensitivity o Nothing happens on first contact with antigen- you can touch poison ivy once and not get it o T-cell mediated: Tcyt and Th o Reaction mediated by release of lymphokines and/or direct cytotoxicity. o Beryllium causes granulomas in the lungs (kind of irrelevant) o (Poison Ivy): Mechanism 1. Pentadeca catechol molecules mix with skin protein 2. This activates T cells and T memory cells  T cells cause dermatitis but on secondary contact  Rash is not contagious- the oil is! 

Autoimmunity:

 o Immune system stops tolerating your own cells & attacking them o Genetic disposition o Triggers: UV light, stress, hormones, metals, food, poisons & pesticides o Prevalence- women have more issues with autoimmune issues  Hypotheses: 2 X chromosomes- one X is dominant- immune system may not tolerate the other X cells o Mechanisms Leading to Autoimmune Disease:  Original insult- drug induced (hydralazine, a-methyldopa, procainamide) can cause changes in red blood cells -> lupus like attack  Virus-induced changes in cell surface antigens causes production of antiidiotypic antibodies.  Supposed to initiate an immune response  Transformative viruses get into your DNA and alters MHC components on some cells  Anti-idiotypic antibodies > looking for specific antigens on specific tissues  Similarities between exogenous antigens and self-antigens (cross reactivity).  Rheumatic fever: group A streptococcus- has M capsular protein on its surface o Group A streptococcus structural similarity to human myocardial proteins

o The antibodies that are trying to kill the bugs are also trying to kill your cardiac muscle  Genetic factors –familial  Products of the MHC locus: Lupus and type I diabetes (predisposition toward the disorders)  Inappropriate immune function may involve histocompatability-complex-linked immune response genes (e.g. C4 & C2 genes), can be triggered by ultraviolet light. (WHAT HAPPENS?)  Complement components- on the same locus as MHC I & II  Abnormal immunoregulation – B cell overactivity & lack of Treg  T & B cells spontaneous activation  Could be because the thymus didn’t educate T cells properly  Decreased T cell function  Hidden antigen theory (who attacks who?)  Places in the body (Central nervous system, testes, cornea) are immunologically privileged sites: blood supply is tightly controlled  Finish development & barriers are closed- break of barriers may compromise immune system o Because the immune system in these areas never seen this crap before o Potential immune attack  Viral breach of these barriers may expose the immune system to a potential immune attack  MS- T cells clones in CNS that recognize and destroy the myelin sheath  Classification of Autoimmune Diseases o MHC (I) ankylosing spondylitis, Reiter’s syndrome   Psoriasis vulgaris (associated with HLA-B13, B16, B17) o MHC (II): Organ specific  Thyroid  Systemic (systemic lupus erythematosis – variety of autoantibodies to DNA, cytoplasmic antigens, etc.)

 Systemic Lupus Erythematosus (SLE) o Antibodies produced against everything in your body  Nucleic Acids, RBCs, WBCs, platelets, phospholipids, coagulation proteins o Damage caused by immune complex deposition (Type III hypersensitivity) o Everything is getting attacked by the antibodies, getting stuck in blood vessels and causing inflammation o UV exposure is a precursor > butterfly rash o Testing: (ANA test- antinuclear antibody test)  Test: take blood- some off the shelf cells- fix them, permeabilize them and incubate them with the patients’ blood (hoping antibodies are present)- throw in Florescent second antibody (antibody against human antibodies & has a tag on it)  Looking for ring type pattern- looking for antibodies against the nucleus  This is the so-called "rim" pattern that is more characteristic of systemic lupus erythematosus (SLE) than other autoimmune diseases.

 Diabetes Mellitus (Type 1) o You have destruction of the beta cells in the pancreas o Polygenic disease – 20 different chromosomal regions have been identified o IDDM1 region: Things that includes the MHC genes determining resistance/ susceptibility to diabetes o IDDM2 region, includes insulin gene & insulin growth factor binding proteins o You already have autoreactive B or T cells present o Type I diabetics are- diagnosed after a severe viral infection  Activation of T cells surrounding the autoreactive B cells lead to their activation o Pathogenic Events Leading to Type 1 Diabetes Mellitus  Autoreactive T cells are present  Viral infections of the beta cells or neighboring tissues will cause the activation of the T helper cells (normal)- fighting the virus and doing normal things  TH cells deliver co-stimulatory signals to autoreactive T cells, resulting in upregulation and accumulation of more autoreactive T cells  Problem: autoreactive T cells present will stimulate Tcyt > if Tcyt are autoreactive, they will cause damage to the beta cells  DAMPS: damage associating molecular patterns  Release cytokines and damage the beta cells and further the inflammatory response  T helper cells are activated  Th1: pushing autoreactive Tcyt to cause damage  Th2: T cell killing and antibody production  Monocytes/macrophages infiltrate to fix beta cells, releasing cytokines and reactive intermediates that can damage beta cells o Other Possible Pathogenic Mechanisms:  Molecular mimicry (leading to cross-reactivity)  Alteration of self-antigens (defective MHC expression on cells)- viruses can alter DNA  Breakdown in central tolerance  Diabetes is a symptom that you’re losing tolerance throughout your body  Trafficking of dendritic cells (APC) from beta cells to pancreatic lymphnodes (APC)- could be farther activating the T cells  Could be carrying inappropriate types of peptides and showing them to Tcells- further activating them  Sensitivity of beta cells to free radical or cytokine induced damage  Defects in peripheral tolerance (aberrant T-cell activation)- May not be central but T cells may be spontaneously activated (not just due to the virus) o Autoantibodies Present in Diabetes Mellitus  Anti-islet cell antibodies – detected by indirect immunofluorescence, present in 90% of patients  Anti-IA-2a (part of MHC complex) and IA-2b (phogrin) antibodies – b cell-associated tyrosine phosphatases, 60-70% of patients  Anti-glutamic acid decarboxylase antibodies – 84% of patients  Anti-enzymes antibodies  Anti-insulin antibodies (prior to insulin treatment) – 92% of patients  Because most insulin back in the day was isolated from pig  Coexistence of anti-insulin and anti-islet cell autoantibodies has a strong predictive value for future development of diabetes BUT do not mediate b-cell destruction  Alloimmunity (immunity about someone from the same species) 1. Fetal and Neonatal Diseases: 2. Graves Disease – Antibody against thyroid-stimulating hormone receptor, neonatal hyperthyroidism  Mother has disorder- IgG is involved- can cross through the placenta and harm the baby 3. Myasthenia Gravis – Antibody binds with receptors for nicotinic acetylcholine receptors on muscle cells  Mother has disorder- IgG is involved- can cross through the placenta and harm the baby 4. Immune Thrombocytopenic Purpura – Antiplatelet antibody, destroys fetal cells

Mother is not necessarily directly attacking the fetus as foreign but the mother themselves may have this disorder and the antibodies are crossing the placenta 5. Alloimmune neutropenia – Anti-neutrophil antibody destroys neutrophils in fetus (if mother has lupus- lots of IgG that cross placenta to attack the fetus) 6. Systemic lupus erythematosus (SLE) –Autoantibodies cause abnormalities in fetus 7. Rh & ABO Alloimmunization – Erythroblastosis fetalis- blood transfusion to fetus to keep them stable until they’re born Transplant Rejection (most will fail within 10 years) 1. Hyper acute – Immediate failure of a graft, usually occurs in the presence of pre-existing antibody to donor HLA antigens in the graft. Especially in multiple transplants 2. Accelerated – Occurs within days, reactivation of presensitized T cells (presence of memory T cells from previous transplant) 3. Acute – Occurs within 2 weeks after transplant, immune response is mounted against unmatched MHC or HLA antigens, primary activation of T cells, antibody and cell-mediated. 4. Chronic – May occur months or years after transplant, characterized by slow progressive organ failure, typically a Type IV hypersensitivity cell-mediated reaction, alloreactive T cells, antibodies and immune complexes involved. T cells doing their jobs and trying to kill a foreign object  Not only you are attacking the graft but the graft is attacking you too (liver) Immunodeficiency Diseases: o Primary: genetic o Secondary: occurs after birth, caused by diseases (cancer)  HIV o Types of Deficiencies could be 1 or combination of:  B Cell  To recognize this, you should make sure you don’t have an underlying T cells deficiency o Because T cells will drive B cells  T Cell  Complement  Phagocytosis Figure: Immunodeficencies can be caused by o Failure of stem cell developmet: reticular dysgenesis o Failure of other stem cells to develop  DISEASE o Missing thymus (Georgia syndrome) o Problem with human bursa equivalent (probably somewhere in the bone marrow)  Gamma Globulin anemia o Later failures: terminal differentiations  This would cause problems in the memory or immunoglobulin producing cells B Cell Deficiencies: (primary) o Transient Hypogammaglobulinemia –makes child susceptible to bacterial and respiratory infection, self-limiting, reduced expression of co-receptor CD19.  Baby is supposed to start making antibodies at 6 months- delayed to age 2-3 (after age of 3, kid is fine) o X-Linked Hypogammaglobulinemia - MALES ONLY, called Bruton’s Disease –Low Ig levels, low or absent B cells and plasma cells, pre-B cells develop but do not mature, mutation of Btk (Br ut ont yr osi neki nase)gene on X chromosome, no antibody light chain production- required for antibody functioning.  Males only- need carrier female and affected male to have baby o Common Variable Immunodeficiency - “Acquired hypogammaglobulinemia” – normal levels of B cells, no plasma cells, reduced levels of serum Immunoglobulins, failure of B cell differentiation, various genes involved, defect in B cell co-stimulatory molecules on the surface molecules.  Shows when people are older- teens  Normal level of B cells but they aren’t making plasma cells- no serum immunoglobulin 

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Selective IgA Deficiency - MOST COMMON – lack of both serum and secretory IgA, failure of terminal differentiation of IgA-secreting B cells, occasionally familial, 2 genes identified.  Failure of IgA-secreting cells development  B Cell Deficiencies: (secondary) o Decreased synthesis of immunoglobulins – Occurs with lymphomas (cancer)  Immature cells-genetically changed- no antibodies production o Increased loss of immunoglobulins - Nephrotic syndrome lupus (leaky kidneys)  Big problem for people with lupus o Production of defective antibodies  Multiple myeloma - Production of Bence Jones proteins, only monoclonal antibody light chains  No functioning B cells components o...