In fetal development, innate and cellular immunity start developing first with macrophages in the liver and blood and T-cell precursors in the liver by 5-6 weeks gestation. At 9-10 weeks, compliment synthesis begins, B precursors appear in the liver, and T precursors appear in the thymus. By 12-14 weeks, the fetus has macrophages in lymph nodes and APC MHC class II, Pre-B cells with IgD, IgG, and IgA; CD4+ and CD8+ T cells in the liver and spleen, and the start of mother's IgG transfer. By 16-17 weeks, fetus has mature macrophages in the liver and circulating neutrophils, Large numbers of B cells in the spleen, blood and bone marrow, and T cells in the blood and lymph tissues with rearrangement of receptors. At 20-30 weeks, babies B-cells secrete antibodies, there is a gradual increase of T cells secreting lymphokines, and a gradual increase of IgG transportation from the mother.
When babies are born prematurely, they lack physical barriers (skin), stomach acidity (less pepsin and trypsin), normal flora, and IgA (needed in respiratory and urinary tracts). Leukocytes are less able to concentrate, are less bactericidal, and less phagocytic. Dendritic cells have low expression of co-stimulatory molecules (eg. CD40) to activate naive T cells and also produce IL-4 and IL-10 that activate Th2 more so than IL-12 that activates Th1. Th2 cells produce IL-4, which induces apoptosis in Th1 cells. This promotes Th2 response more than Th1, leading to reduced production of pro-inflammatory cytokines. Reduced CD40 expression by B cells reduces T-dependent antibody responses, decreasing antibody production, isotope switching, and affinity maturation.
~Light Microscopy - fresh or stained specimens are examined directly to visualize bacteria, protozoa, or host cells with good specificity but low sensitivity
~Culture - recovery of live organisms requires media (host cells if viral culture), incubator, and sometimes light microscopy to identify microbes. It has high specificity and higher sensitivity than light microscopy but lower sensitivity than nucleic acid amplification tests (NAATs). Necessity of live organisms decreases risk of false positive (due to remnants of dead organisms still in system)
~Immunoassays - detect antigens or antibodies in biological specimens. Antigen indicates current infection while antibodies indicate past infection (note: not all infections cause antibody production).
ELISA (enzyme-linked immunosorbent assay) - to detect antigens, attach the Fc portion of a specific antibody to the ELISA plate so that the Fab region can bind to specific antigen in the sample if present. Then add the primary detection antibody that will bind to that antigen followed by a labeled secondary detection antibody that binds to the primary detection antibody's Fc region. To detect antibodies, attach the antigen to the plate first and then follow with the sample that may contain the antibody. Follow with a labeled antibody that binds to the Fc region of the sample antibody.
Rapid immunochromatographic strip tests - a liquid sample travels up through absorbent material and if the antigen is present, it will bind to a certain area containing antibodies and turn a color (eg. rapid strep)
Particle agglutination tests - to test for presence of an antigen (eg. staph aureus), add a solution with antibody that will make the antigen clump up if present.
~Nucleic acid amplification tests (NAATs) - Molecular detection assays for bacteria, viruses, and eukaryotic pathogens that target and amplify microbial DNA or RNA using PCR, rcpt., transcription mediated amplification, strand displacement amplification, etc. These are more sensitive than microscopy, culture, or antigen detection and more specific. They don't require live organisms (which can lead to misleading positive results even after all the pathogens have been killed). Increased sensitivity allows for use with non-invasive specimens (urine sample rather than endocervical/urethral swab)
Vaccines that are composed of capsular polysaccharides elicit B cell responses in a T-cell-independent manner (no class switching, affinity maturation, etc.); glycoconjugate vaccines (polysaccharide-peptide antigens) recruit CD4+ T cells in T-cell-dependent antibody responses; toxoid, protein, inactivated or live attenuated viral vaccines elicit a CD4+ T-cell-dependent response with higher-affinity antibodies and immune memory; and live attenuated vaccines can also generate CD8+ cytotoxic T cells. (Most vaccines cause an IgG response and some induce IgA or activate T cells.)
Live vaccines induce better innate responses, more antibodies, and longer antibody persistence than inactivated. Protein vaccines recruit T helper cells and induce a germinal center to provide a better antibody response than polysaccharide vaccines.
Antibodies neutralize microbes and their toxins, opsonize microbes for phagocytosis, promote death by NK cells and activate complement, which leads to MAC complex formation to lyse microbes, opsonization, and inflammation.
~Inactivated vaccines include whole bacteria/viruses that are produced by growing large number of them and killing them with heat or chemical fixation. Inactivated bacterial vaccines provide limited, short lived protection and are not used routinely in the US. Inactivated viral vaccines also don't provide as good or long-lived protection but some are used in the US (flu, rabies, polio (Salk) vaccine.
~Attenuated, live vaccines - produced by repeated passages of the organism through cell culture or lab animals until a non-virulent organism (weakened but can still replicate) is isolated. They are effective and generate long term protection that may be lifelong (but sometimes need boosters). Live viruses can infect cells so that a good antibody response and CTL response is produced. Examples include measles (rubeola), mumps, rubella, chickenpox, rotavirus, and live (oral) influenza vaccine. Live vaccines can also be bacterial (eg. BCG for TB). Those with immune deficiencies should not get live vaccines because they can become infected (if CD4+ is above 15% of normal, then it's OK). Those seeing patients who are immunocompromised shouldn't get live vaccines because they might spread it to them.
~Purified antigen/subunit vaccines - Toxoids are inactivated usually via chemical modification and are very effective immunogens (diphtheria, tetanus).
Purified polysaccharide antigens - not efficient at inducing longer protection because T independent, but they are more effective when coupled to proteins (adjuvant) to create conjugate vaccines. Purified antigen and subunit vaccines are very safe but have a short shelf-life, are hard to produce, and con't stimulate CTL response because they are recognized as exogenous antigens.
~Synthetic/recombinant antigen vaccines - the active part is a synthesized protein or amino acids that mimic antigenic epitopes on a particular virus or bacteria. An example is Hep B vaccine. These are safe but have a short half life, are hard to make, and don't stimulate a significant CTL response.
~Polyvalent/combination vaccines - these reduce the number of injections but not all can be combined because immune response to one component may hinder the response generated to another. There is a combination vaccine with antigens for diphtheria, tetanus, pertussis (acellular vaccine), hep B (recombinant protein), and Haemophilus influenza b (Hib)
Vaccines are designed to induce a potent and protective immune response to potential microbial pathogens by exposing the host to antigenic, but non-pathogenic material in order to prevent or modify the disease process (eg. Pertussis vaccine only decreases severity of disease, doesn't prevent it). This instills active immunity - the body's own response to the potential pathogen.
Passive immunity is created via transfer of pre-formed antibodies (polyclonal antibody, monoclonal antibody, hyper-immune antibody) to an individual. Passive immunity is short lived and doesn't induce memory. Passive immunizations are used when there is immediate need for protection (eg. rabies immune globulin - RIG. Also, protection against toxins like tetanus, botulism, diphtheria, and snake venom), when person is unable to produce an adequate immune response, or when there is no safe/effective vaccine to give active immunity (monthly respiratory syncytial virus monoclonal antibody for premature infants with chronic lung disease). Passive immunization is also used to prevent Rh- mothers from becoming sensitized to fetal Rh+ erythrocytes (Rho-Gam).
COX-1 (cyclooxygenase 1) is constitutively expressed in almost all tissues, is the only COX present in platelets (creates Thromboxane A2), and is predominant in the gastric mucosa where it produces prostaglandins that protect the gastric mucosa. COX2 is only constitutively expressed in the brain, kidney, bones, reproductive, organs and some neoplasms but is highly inducible by pro-inflammatory stimuli (LPS, TNFalpha, IL-2, IFN-gamma) at sites of inflammation, producing PGs that induce pain, fever, etc. Non-Steroidal Anti-Inflammatory Drugs include Aspirin (Acetylsalicylic acid), Ibuprofen (Advil, Motrin), Naproxen (Aleve), and Indomethacin (indocin). Some NSAIDs are specific COX-2 inhibitors that block the production of pro inflammatory PGs without interfering with gastric protection or lately activity; however, these cause hypertension, vasoconstriction, and increased CV events. Most are non-specific and block both COX, so long-term therapy is limited by side effects, especially erosion of gastric mucosal protection. NSAIDs have a black box warning for severe GI events (eg. bleeds) and cardiovascular thrombotic events, MI, and stroke. They can also cause renal, hepatic, CNS, hematologic, and hypersensitivity effects. Acetylsalicylic acid transfers a functional group onto COX to irreversibly prevent it from converting arachidonic acid to PG and Tx. The Leukotriene pathway is unaffected, which can produce inflammatory mediators especially in those with asthma. The reduction in PGs reduces inflammation and edema but blocks cytoprotection of the GI tract, causing gastric upset, bleeding, and ulcers. Can also cause prolonged bleeding (decreased platelet function lasts 4-6 days) and tinnitus. At 30-100mg/day, Aspirin is an antithrombotic. At .3-.6g/day, it is an antipyretic (reduce fever) and analgesic, and at 3-5g it is anti-inflammatory. Aspirin has been approved to treat pain, inflammation, fever, prevent/treat acute coronary syndromes, acute ischemic stroke, rheumatoid arthritis, rheumatic fever, osteoarthritis, and as adjunctive therapy in revascularization procedures. Unlabeled uses include prevention of preeclampsia, colorectal cancer, and thromboembolism, and treatment for Kawasaki disease. Reyes syndrome - A rare acute illness that occurs in children after a viral infection that was treated with aspirin to lower fever. Children can have respiratory depression and acidosis, CNS depression, sweating, dehydration, electrolyte imbalance, hypotension and vasodilation, coma and death. Today, aspirin is not used in children with viral illness - use acetaminophen (tylenol) or ibuprofen.
Some can have a hypersensitivity to aspirin so that even small quantities can cause nail congestion and acute, severe bronchospasm - Aspirin Sensitive Asthma. They are also at risk for anaphylactic reactions and angioedema. Other NSAIDs will also cause this in these people. But they can be desensitized over time with daily administration of aspirin and cross-tolerance to other NSAIDs usually occurs.
Chronic poisoning (salicylism) is also possible especially in children, causing nausea, vomiting, headache, tinnitus, hyperglycemia, and delirium.
Corticosteroids are derivatives of adrenocorticosteroid hormones from the adrenal cortex used to suppress the immune system in severe allergy, inflammation, and organ transplantation. They can be combined with other immunosuppressant drugs. Prednisone and prednisolone are examples. Corticosteroids have fewer side effects and require lower doses to be anti-inflammatory than NSAIDs. Glucocorticoids, a type of corticosteroid (eg. cortisol), decrease transcription of inflammatory cytokines (IL-1, IL-2, TNF-alpha, IFN-gamma). But blocking their action affects many organ systems and cell processes, including almost every player in the immune system. In the inflammatory cycle, corticosteroids inhibit COX-2, phospholipase, chemotactic agents, and WBC migration; decrease cytokine expression; induce T cell death; and destabilize mast cells and neutrophils. They affect cell-mediated immunity more than humoral, increasing the risk for viral infection. Sometimes they are used in conjunction with antimicrobial therapy and may prevent use of live vaccines. In tissue repair, they inhibit protein synthesis, fibroblast proliferation, and collagen synthesis.
Using glucocorticoids chronically can be toxic and cause fat redistribution, hypertension, glucose intolerance, impaired wound healing, osteoporosis, cataracts, gastric ulcers, infection risk, CNS effects, and growth inhibition.
Disease Modifying Anti-Rheumatic Drugs (DMARDs) are used to treat rheumatoid arthritis. These include Etanercept (Enbrel), Infliximab (Remicade), and Adalimumab (Humira), all of which inhibit TNF.
Methotrexate is an oral immunosuppressive agent that inhibits dihydrofolate reductase, which is needed to produce folic acid used in thymidine, prune, and pyrimidine base synthesis (DNA, RNA, and proteins). This is why, in large doses, it's used in chemotherapy. Low doses are used for immune suppression in autoimmune diseases by inhibiting T cell activation, down-regulating B cells, etc. It's often used with other agents and can adversely affect the liver and bone marrow.
Mycophenolate Mofetil (CellCept) inhibits Inosine monophosphate dehydrogenase (IMPDH) that is needed to make guanine nucleotides. This inhibits the DNA synthesis and functioning of B and T cells. CellCept is used to prevent transplant/graft rejection and to treat autoimmune disease. It can adversely affect the GI tract and bone marrow.
In the US, HIV is usually transmitted via male-to-male sexual contact (60%), then heterosexual contact (30%), then injection drug use (10%). Perinatal transmission (vertical) and exposure to infect blood products/fluids are less common. Without AZT, vertical transmission risk is 1 in 4. With ATZ it's less than 1 in 10, and with combination antiretrovirals its less than 1 in 100. A needle stick carries a 1 in 200 risk of transmission without AZT PEP but a 1 in 10,000 chance with AZT PEP. Anal sex (vs. vaginal), presence of STIs, and uncircumcised (vs. circumcised) increase the rates of transmission. Partners can decrease their risk of infection with pre-exposure prophylaxis (PrEP - Truvada) Transmission also depends on viral load (highest 2-3 weeks after infection). Rates of diagnosis blacks>multirace>hispanic>native hawaiian>American Indian>White>Asian. HIV prevalence is greatest in southern states, California, DC, NY, Maryland, and NJ.
HIV is usually acquired through mucosal membranes of the vagina and foreskin epithelia, where macrophages, DCs, NK cells mount the innate immune response.
During the acute phase (acute retroviral syndrome), 60-90% will have symptoms beginning 2-3 weeks post-exposure (concurrent with increased viral load) similar to mono with unspecific signs and symptoms (fever, sore throat, lymph nodes, faint rash, mucosal ulcers).
HIV can have clinical but not virological latency - the virus is replicating all the time but no symptoms may be present again for years.
TB infection is common with HIV (even without AIDS) and chest x-rays may not show the classic upper lobe cavities and delayed type hypersensitivity skin tests may be negative because of immune suppression.
The occurrence of recurrent/severe bacterial and viral infections, thrush, parotitis, hepatomegaly/splenomegaly, wasting, developmental delay (children), lymphadenopathy, lymphocytic interstitial pneumonia (LIP), autoimmune disease, malignancy, and opportunistic infections signifies the onset of AIDS.
Focal CNS processes can occur, like toxoplasmosis, Primary CNS lymphoma, and Progressive multifocal leukoencephalopathy.
Physical signs include Kaposi's sarcoma, leukoplakia, thrush, angular cheilitis (cracked lip corners), shingles, seborrhea, and herpes simplex virus.
Fungal infections are common in AIDS (CD4 < 200), including cryptococcus (causes meningitis and disseminated infection), candida (esophagitis), and Pneumocystis jiroveci pneumonia (PCP - the most common opportunistic infection causing pneumonia). PCP causes shortness of breath, non-productive cough, sometimes fever, hypoxemia (O2 desaturation), and elevated lactate dehydrogenase. On X-ray, the heart often has a wispy rather than crisp border. Bacteria or Septra are used prophylactically in those with CD4 < 200.
Viral infections common with AIDS include Cytomegalovirus (CMV) that causes retinitis, esophagitis, colitis, and affects the CNS. CMV is an enveloped dsDNA virus that most people have been infected with but that becomes reactivated in 80-100% of those with HIV when they have a very low CD4 count (<50). DNA viruses can establish latency and become oncogenic - HHV-8, EBV, HPV, HBV/HCV.
Human herpes virus (HHV)-8 is also common and causes Kaposi's sarcoma and primary effusion lymphomas. Kaposi's sarcoma can present in those with a CD4>200 and includes lymphadenopathy and edema and can involve the lungs and GI tract. Cutaneous forms may resolve with immune recovery.
Protozoa that cause infections in AIDS patients include Toxoplasma gondii and Cryptosporidia in the GI tract (causes diarrhea).
Bacterial infections include mycobacterium avium complex. Mycobacterium avium complex involves diffuse infection of multiple organs (GI, spleen, liver, marrow) in those with CD4<100. Symptoms include fevers, night sweats, diarrhea, weight loss, high alkaline phosphatase, and anemia. Diagnosis is done with lysis centrifugation culture. In those with CD4<50 Azithromycin is taken prophylactically.
Antibody defects/deficiencies are the most common type of primary immune deficiency (PID). Common symptoms include pyogenic infections like recurrent otitis media, sinusitis, pneumonia, cellulitis, osteomyelitis, and meningitis; frequent viral infections; infection by encapsulated bacteria; and chronic diarrhea caused by giardia (protozoa).
Examples include Agammaglobulinemia, Hyper-IgM syndromes, IgA deficiency, common variable immunodeficiency, Specific antibody deficiency, and transient hypogammaglobulinemia of infancy.
You diagnose these using CBC with differential, age-adjusted quantitative immunoglobulins, specific antibody titers, and complement pathway functional assays (CH50, AH50, MBL). You can test specific antibody production using protein-based titers (diphtheria, tetanus), polysaccharide titers (isohemagglutinins - ABO antibodies based on blood type), pneumococcal responses. An adequate response will be a >4x rise in titer/Ab to a single serotype. Pneumovax tests pure polysaccharide responses to the top 23 serotypes in those >2 years of age (younger children don't respond as well to polysaccharide vaccines).
Lack of T cells or disfunction causes combined immunodeficiencies because CD4+ cells are needed for B cell activation and class switching. T cell dysfunction leads to infections with intracellular organisms - Viruses (HSV, V-Z, CMV, EBV), protozoa (cryptosporidium, toxoplasma), mycobacteria (TB), fungi (candida, pneumocystis jiroveci), gram negative enteric bacteria, and polysaccharide encapsulated bacteria. Also causes failure to thrive (especially with diarrhea), anergy by T cells, graft vs. host disease (mother's T cells can attack child's skin, causing eczematous rash), increased B-cell malignancies, eosinophilia, thrombocytopenia, eczema, alopecia, and thrush.
Examples include SCID, Omenn syndrome, DiGeorge syndrome, and Wiskott Aldrich syndrome.
Diagnostic evaluations include those that look at B cell function because B cells can be impaired: CBC with differential, age-adjusted quantitative immunoglobulins, and specific antibody titers (protein (eg. tetanus) and polysaccharide vaccines).
To examine T cell mediated immunity: Nonspecific lymphocyte mitogen proliferation assays test for function against antigens that should cause activation despite antigen specificity. Function is measured using the level of labeled thymidine incorporation during proliferation. Delayed type hypersensitivity skin tests are used to detect candida reactivity and nucleic acid enzyme assays are used to detect Adenosine Deaminase deficiency.
DiGeorge syndrome is caused by a defect in the 3rd and 4th pharyngeal pouches during embryogenesis usually caused by a deletion of chromosome 22q11.2. Clinical features include dysmorphic face, hypocalcemia (no parathyroid), depressed T-cell immunity (if hypo plastic/aplastic thymus), and congenital heart disease. Diagnoses can be confirmed with a lateral chest x-ray (no thymus).
Partial DiGeorge is most common and includes thyme hypoplasia (normal corticomedullary differentiation, Hassall's corpuscles, normal function), CD4>400, adequate T function, normal B-cell numbers and function, and no infections.
Complete DiGeorge is uncommon and includes thyme aplasia, so CD4 < 400, B cell numbers are normal but antibody response is decreased, leaving them susceptible to infections and graft vs. host disease. These patients must get thymus transplants.
Chronic Granulomatous Disease - causes recurrent bacterial infection with catalase positive organisms (Staph, Serrate, Aspergillus) and granulomas of the skin, liver, lungs, and lymph nodes. Phagocytic cells ingest but can't kill bacteria because they can't form oxygen radicals. An X-linked or AR gene defect prevents electron transfer by phagocyte NADPH Oxidase (PHOX) needed to produce the superoxide (O2+). CGD is diagnosed using nitroblue tetrazolium dye test, superoxide radical formation (chemiluminescence) test, or flow cytometry (dihydrorhodamine 123 assay).
Leukocyte Adhesion Deficiency - caused by an absent beta subunit (CD18) of 3 cell surface glycoproteins (beta2 integrins). Neutrophils can't migrate to inflammatory stimuli or adhere to the vascular endothelium. It's diagnosed using recurrent soft tissue infections, delayed umbilical cord separation, severe periodontal disease and no pus formation despite high white blood cell counts.
HyperIgE syndrome (Job syndrome) - causes recurrent staph abscesses, sinopulmonary infections, and severe eczema; regained primary teeth; recurrent Candida; and recurrent bone fractures. IgE levels are very high, usually >2000, and they have peripheral eosinophilia. The underlying defect affects CD17 and neutrophil migration.
Compliment disorders - deficiencies in the classical pathway (C1, C4, C2) can cause autoimmunity. For example, defects in C1 esterase inhibitor lead to Hereditary Angioedema that causes massive swelling without itching or hives. Deficiencies in C3 can lead to problems with encapsulated bacteria and autoimmune disease. Deficiencies in late compliment (C5b-C9) lead to susceptibility to neisserial infections.
Defects in innate immunity are diagnosed using CBC with differential, neutrophil function tests (oxidative burst, chemotaxis assays, and presence of CD18beta), and assays for compliment.
HIV/AIDS, malnutrition, immunosuppressive therapy, malignancy, autoimmune disease
Disorders of biochemical homeostasis leading to chronic imbalance of hormones, nutrients, and toxic metabolic waste products like diabetes, dialysis/uremia, cirrhosis. Diabetes is associated with decreased neutrophil function that correlates with the level of hyperglycemia, poor peripheral circulation that increases the risk of skin ulceration, and candidiasis and other fungal infections. Hemodialysis reduces T cell, neutrophil, and dendritic function and decreases Ig production. Chronic peritoneal dialysis removes immunoglobulin and complement with the dialysate, compromising peritoneal neutrophil function. Cirrhosis increases risk of bacterial sepsis and peritonitis and leads to higher endogenous glucocorticoids and low complement levels.
Disorders of protein loss - nephrotic syndrome, peritoneal dialysis, protein losing enteropathies (poop it out - IBS, celiac, intestinal lymphangiectasia), and severe dermatitis can lead to hypogammaglobulinemia that often presents as low IgG and IgA with near normal IgM. Patients may not have increased susceptibility to infection and have a positive but low titer. To determine that it's protein loss causing decreased Ig, give them an IVIG and see how rapidly the levels drop. In nephrotic syndrome (kidney disease with protein loss), patient have very low Igs and depressed cellular immunity from vitamin D and other serum factor loss. Patient are treated with immunosuppressive drugs like glucocorticoids that further increase the risk of infection, leading to recurrent respiratory tract infections, urinary tract infections, Varicella, peritonitis, and sepsis, especially with encapsulated bacteria like strep pneumonia. In those with recurrent infection and low IgG, IGIV may be helpful.
Trauma/burns - cellular necrosis from trauma causes widespread activation of monocytes and macrophages that release inflammatory cytokines (IL-1, TNF). Burn trauma causes more severe immune suppression than mechanical trauma because they disrupt a large area of skin that provides nonspecific defense (increased loss of fluids and proteins also increases infection risk).
Environmental exposures - ionizing radiation from X-rays and gamma rays damages DNA, impairing cell division and immune function; may induce apoptosis; cause DNA damage leading to malignancy; damage local barriers in areas with high rates of cell division (gut>skin), and decrease B and T cells (bigger impact on B cells and T cells recover faster), diminishes primary antibody response, and affects lymph tissues. The functioning of macrophages is unaffected. UVB radiation from the sun is the major risk factor for skin cancer and can diminish function of all skin immune cells. Toxic chemicals also impact immune system.
Splenectopy/hyposplenism - atrophy can be caused by sickle cell disease, autoimmune disease, severe celiac, IBS, chronic graft-vs-host disease, and untreated HIV infection. There is a greater risk of sepsis from encapsulated organisms. Immune suppression is managed with immunization and sometimes antibiotic prophylaxis.
Life events - cellular immunity is depressed during pregnancy to prevent rejection of the fetus, but this increases risk of infections controlled by cellular immunity (Hep A and B, influenza, herpes, chlamydia, listeria, TB, and fungal, protozoan, and helminthic infections). Stress diminishes cellular immune function, NK cell activity, and lymphocyte mitogen responses.
Infections (other than HIV) -
Measles suppresses the immune system, leading to superinfection, most often pneumonia, gastroenteritis, otitis media, gingivostomatitis, and other upper respiratory infections (staph aureus and strep pneumonia). Measles virus infects T cells and dendritic cells so that T-dependent areas of lymph nodes and spleen are depleted leading to T cell lymphopenia, T cells do not respond as well to mitogens, antibody production is diminished.
Herpesviruses - can cause transient depression of cell-mediated immunity, especially CMV.
Parasites - immune suppression from protozoa infection is greater than any other microbe (but HIV). Decreased cell-mediated immunity in malaria leads to increased susceptibility to infection, delayed graft rejection, and higher rate of malignancies.
Superantigens (from staph and strep) significantly stimulate the immune system but ultimately lead to a decrease in T cell number and activity and a decrease in neutrophil function.
Type I - immediate hypersensitivity is the most common type, causing allergy/atopy via mast cell activation by IgE that binds to an allergen. Mast cells release vasoactive amines, lipid mediators, and cytokines (eg. histamine) initially, causing cytokine-mediated inflammation from eosinophils and neutrophils. It can cause allergic rhinitis, atopic asthma, and anaphylaxis.
Type II - antibody-mediated diseases in which IgM and IgG antibodies bind to cell surface or extracellular matrix antigens such that complement and neutrophils/macrophages' Fc receptors bind to them and become activated. This leads to opsonization/phagocytosis of self cells and inflammation/tissue injury that is localized to those tissues. One example of this is
Type III - immune complex-mediated diseases - IgM or IgG antibodies bind to antigens in circulation and form immune complexes that settle and deposit in blood vessels, activating compliment and recruiting/activating macrophages/neutrophils, which cause vasculitis because of lysosomal enzymes and reactive Oxygen species.
Type IV - T cell-mediated diseases causing delayed type hypersensitivity - CD4+ cells become activated by macrophages presenting self or foreign antigens and release cytokines (like INF-gamma) that recruit/activate neutrophils and macrophages that cause inflammation. Alternatively, CD8+ cells can become activated by self or foreign antigens on cells, initiating cytolysis of those cells.
Goodpasture's syndrome - antibodies are made against the basement membrane in the kidney and lung (anti-GBM disease (glomerular basement membrane), leading to inflammation, fatigue, bloody urine/kidney failure, and blood in the lungs. It's treated with Retuximab (antibody to CD20) and plasmapheresis to remove the plasma with anti-GBM and replace it with plasma without it.
Idiopathic Thrombocytopenic Purpura (ITP) - antibodies target platelets for destruction, which can lead to bloody nose, some fatigue, and pinpoint dots on the skin, but usually this is asymptomatic. Purport are caused by hemorrhage of small blood vessels in the skin that are inflamed and have become plugged with colts.
Autoimmune hemolytic anemia (AIHA) - antibodies target red blood cells so that neutrophils break down their membranes and change their shape and size.
Antibodies can also cause abnormal physiologic responses without cell/tissue injury. For example, in Graves disease, antibody against the TSH receptor can stimulate the receptor without the hormone, leading to hyperthyroidism. In Myasthenia graves, antibody binds to ACh receptors in muscles at the nerve junction, inhibiting Ach binding.
Serum sickness - immune response to a large amount of injected antigen (like serum of other people or animals or penicillin), causing a variety of symptoms including fever, hives (C3a releases histamine from mast cells), joint pain, spelnomegaly, asthma, and disorientation (from compromised O2 delivery to brain b/c of vasculitis in small blood vessels). When there is antigen excess and a rapid IgG response, small immune complexes are formed and taken up by endothelial cells in various body parts and become deposited in those tissues, activating complement there and leading to inflammation (this is in contrast to instances when there is a large amount antibody relative to antigen and large immune complexes form and are taken up (cleared) by phagocytic cells). Very rarely, this can happen in response to chimeric mAb treatment and cause purpuric rash with neutrophil-rich vasculitis with presence of immune complexes in the vessel walls, hematuria, and proteinuria. You can see if the immune complexes are developing around mouse protein of the chimeric mAb by labeling antibody that is specific to the mouse protein with phosphorescence.
Systemic lupus erythematosus (SLE) - Characterized by defective B and T cell tolerance to self antigens. Loss of self-tolerance occurs when defects increasing apoptosis and/or reducing opsonizing factors and phagocytic activity to clear apoptotic cells leads to an increase in apoptotic cells. In the peripheral tissue, this causes inflammation and CDs in the peripheral tissue phagocytose and express auto antigens to T cells so that T cells lose tolerance. In lymph nodes, auto reactive B cells are exposed to the apoptotic nuclear particles and lose self cell tolerance. B cells produce autoantibodies that mainly target the nuclear constituents. This can cause (SOAP BRAIN MD)
anti-nuclear antibody production (eg. to Smith nuclear antigen),
immunologic (pleuritic, pericarditis, cytopenia (type II hypersensitivity)),
neurologic (seizures, psychosis),
malar rash (butterfly rash that spares nasolabial folds), and
It is most often diagnosed after 20 years old, is more common in blacks and asians that whites, and affects females more than males, especially when women are of childbearing age. Estrogen drugs can increase symptoms, so hormones may play a role. It has a genetic component, and compliment deficiency (C1q, C2, and C4) is the strongest genetic risk factor for developing lupus because a lack of C1q prevents you from clearing immune complexes, increasing the risk for autoimmunity. A gene on the X chromosome may be involved in lupus, and those with lupus have increased prevalence of Kleinfelter's syndrome (XXY) and decreased prevalence of Turner syndrome (XO)
poison ivy contact dermatitis - Urushiol from poison ivy is presented on MHC class I, activating T cells and and causing release of INF-gamma, IL-17, and TNF-alpha that increase inflammation and cause cell destruction. The reaction is delayed and develops over 12-48 hours.
Also what occurs with TB skin tests.
Also involved in pathogenesis of many infectious diseases (TB, leprosy, histoplasmosis), allergic diseases (drug induced nephritis) and autoimmune diseases (autoimmune thyroiditis, polymyositis, MS).
Polyoma virus nephritis - nonpathogenic polyoma virus in the lower urinary tract epithelium can spread to the renal parenchyma in those with immunosuppression (histologically, you se mononuclear leukocytes infiltrating tubules in the cortex). You would diagnose this using immunofluorescence microscopy (fluorescent probe on an antibody specific to the virus), which would show PV in the nuclei of tubular epithelial cells.
Type IV immune response occurs with acute cell mediated transplant rejection. Histologically, you see inflammation with mainly mononuclear leukocytes like neutrophils.
When someone is first exposed to an antigen/allergen (generally a low molecular weight protein), that allergen binds to receptors on B cells and induces them to activate TH2 cells, which release IL-4, IL-5, and IL-13 that stimulate IgE class switching in the B cells. In those who become atopic, greater levels of IgE are produced than normal. The Fc region of IgE binds to receptors on mast cells, leaving the Fab region to bind to the allergen during future exposures. Allergen binding activates mast cells and basophils to release preformed granules of histamine enzymes, proteases, and vasoactive amines that increase vascular permeability and stimulate smooth muscle cell contraction, causing immediate hypersensitivity reaction. They also release lipid mediators (PG, leukotrienes, platelet activating factor) that cause vasodilation, bronchoconstriction, mucus secretion, intestinal hypermotility, and vascular permeability. Later, mast cells and basophils produce and secrete (i.e. not preformed) cytokines (IL-4, IL-5, IL-13, TNF-alpha) that cause inflammation, IgE production, and eosinophil production/activation in the late phase reaction 2-4 hours after exposure. Eosinophils are bone marrow-deprived granulocytes that are recruited by IL-4 and activated by IL-5. They contain preformed cytoplasmic granules that cause tissue damage/remodeling and that are toxic to helminths, bacteria and host cells. Lipid mediators produced on activation prolong bronchoconstriction, mucus secretion, and vascular permeability and cytokines produced upon activation further activate eosinophils and cause chemotaxis of leukocytes. The most common are milk, eggs, peanuts, wheat, and soy. These (except peanuts) have a complex tertiary structure and most people grow out of these. Other common ones are fish, shellfish, and tree nuts. These have a linear structure and most don't grow out of these (also peanuts).
Peanut allergies are seen in 1% of young children and it usually presents at age 15 months. Those with peanut allergy are at risk for future systemic allergic reactions and asthma. 20% of young children outgrow it, generally by school age. People can have localized allergic reactions by touching peanuts and non-life-threatening symptoms by smelling it. But if they ingest even 1/1000th of a peanut, they can have life-threatening reactions.
In a skin pic test, a wheal greater than 3mm is positive. This test has a great negative predictive value, but a positive predictive value of only 50% (you can test positive because you are sensitized to an antigen and have IgE for it but don't have a clinical response). You can also use an in vitro test with serum, but it has similar predictive values.
Anaphylaxis - systemic immediate hypersensitivity reaction characterized by edema in many tissues and a decrease in blood pressure caused by vasodilation that occurs seconds to minutes after exposure.
Bronchial asthma is an inflammatory disease caused by repeated immediate-type hypersensitivity and late-phase allergic reactions in the lung, leading to the clfinicopathologic triad of: intermittent and reversible airway obstruction, chronic bronchial inflammation with eosinophils, and bronchial smooth muscle cell hypertrophy and hyperactivity to bronchoconstrictors
allergic rhinitis - hay fever - most common allergic disease, a consequence of immediate hypersensitivity reactions to common allergens such as plant pollen or dust mites localized to the upper respiratory tract by inhalation
Food allergy - immediate hypersensitivity reactions to ingested foods that lead to the release of mediators from intestinal mucosal and submucosal mast cells of the GI tract, including the oropharynx. Clinical manifestations include pruritus, tissue edema, enhanced peristalsis, increased epithelial fluid secretion, and oropharyngeal swelling, vomiting, and diarrhea.
Urticaria (hives) - an acute wheal-and-flare (bump and surrounding redness) reaction induced by mast cell mediators that occurs in response to direct local contact with an allergen or after an allergen enters the circulation
Generative (central) tolerance develops in the thymus (T cells - deletion and regulatory T cells) and bone marrow (B cells - receptor editing, deletion, and anergy).
In the thymus, double positive thymocytes undergo positive selection in the cortex with the help of cortical Thymic Epithelial Cells (cTEC) such that T cells with weak recognition of Class II MHC (CD4+) or of class I MHC (CD8+) are selected for. Those that survive go to the medulla and undergo negative selection with the help of medullary epithelium (mTEC), such that those that bind strongly to class I or class II MHC are deleted (apoptosis). mTEC contain Autoimmune regulatory (AIRE) proteins that present peripheral tissue self antigens on MHC to the T cells. Those that bind to self antigen either undergo apoptosis (deletion) or become regulatory T lymphocytes (CD4+ T cells only). Natural regulatory T cells (from the thymus) enter the periphery and contain CD3, CD4, and CD25 as well as FoxP3+ (necessary transcription factor) and inhibit responses against self-antigens by inducing CTLA-4 expression in T cells, expressing IL-2 receptors to capture IL-2 (so that it can't stimulate other T cells), and by releasing anti-inflammatory cytokines IL-10 and TGF-beta. (induced regulatory T cells are created in the periphery).
In the bone marrow, B cells undergo receptor editing, deletion, and anergy. In receptor editing, B cells that are too self-reactive either re-express RAG genes to modify their Ig variable region so that it is not self-reactive or are deleted (apoptosis). B cells that don't recognize self antigen become anergic B cells.
Peripheral tolerance occurs in the spleen and lymph nodes.
T cell tolerance development involves anergy, suppression, and deletion. When T cells' TCR binds to the MHC protein on an APC without costimulation by APC's B7 (binds with T cells' CD28), the T cells become functionally unresponsive in anergy. Additionally, B7 on APCs can interact with CTLA-4 on activated T cells to down regulate T cells (anergy) and promote self-tolerance. PD-L1 on many types of cells and PD-L2 on APCs can also interact with PD-1 on activated T cells (and B cells) and induce the same effect. Peripheral T cells can also be deleted. Normally, intracellular anti-apoptotic proteins keep activated T cells alive, but if the T cell isn't co-stimulated, pro-apoptotic protein can be released from the mitochondria and induce apoptosis. Alternatively, FasL (death receptor ligand) and Fas (death receptor) can become expressed when T cells aren't co-stimulated. Two T cells expressing Fas and FasL can then interact with each other and induce apoptosis.
The binding of CD28 on T cells and B7 on APCs can also stimulate the generation of regulatory T cells. Regulatory T lymphocytes that develop in the peripheral tissues (induced rather than natural) contain CD3, CD4, and CD25 as well as FoxP3+ (necessary transcription factor) and inhibit responses against self-antigens by inducing CTLA-4 expression in T cells, expressing IL-2 receptors to capture IL-2 (so that it can't stimulate other T cells), and by releasing anti-inflammatory cytokines IL-10 and TGF-beta.
B cell tolerance involves anergy, deletion, and suppression via inhibitory receptors.
Molecular mimicry occurs when foreign and self peptides are similar enough to result in cross-activation of auto reactive T or B cells by the foreign peptides.
Strep. pyogenes (group A beta-hemolytic strep - GABHS) can cause respiratory, skin/soft tissue, or deep/systemic infections and their toxin can cause scarlet fever or streptococcal toxic shock syndrome. It can also cause immune mediated acute rheumatic fever or post streptococcal glomerulonephritis.
Acute rheumatic fever is most prevalent in children 6-15 years old 2-3 weeks after GABHS pharyngitis. Diagnosis requires proof of prior GABHS and 2 major or 1 major and 2 minor symptoms.
Major - arthritis, carditis, sydenham corea (brain), erythema marginatum (rash), subcutaneous nodules
Minor - arthralgia, fever, increased ESR, CRP, prolonged PR interval. ARF is treated by eradicating/preventing GABHS (penicillin) and suppressing the immune system (aspirin, corticosteroids).
Guillain-Barre syndrome - acute monophonic illness causes progressive polyneuropathy with weakness and paralysis that begins distally and moves proximally. Marked by muscle weakness and absent/depressed deep tendon reflexes. It's caused by an immune response to a preceding infection (most often campylobacter jejuni. also CMV, EBV, and HIV) that cross-reacts with peripheral nerve components because of molecular mimicry. Immune response can be directed toward myelin or axon of peripheral nerves.