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First time I've heard of IgD: 11/26/14. From Dr D'Adamo. =-]


--APC = antigen presenting cell, professional, these have MHC-II pathway and include macrophages and DC's
--B-cells are the lymphocytes that make antibodies (humoral immunity) and remember antigens. They are born and raised in the bone marrow. When a B-cell is activated by the binding of an antigen to its surface antibody, it is activated and becomes a plasma cell. PLASMA CELLS can make a lot of antibodies/immunoglobulins. B-cells can also phagocytize antigen and present it to T-cells, which then secrete cytokines that help the B-cells mature. B-cells can make antibodies against toxins such as diptheria, capsule such as Strep pneumo, and viruses. The order of Ig manufacture is always: M first, then A and G. Once a response has been mounted to a particular antigen, the second response is faster because some cells that "remember" that antigen remain for a long time in the lymph nodes. IgG production with subsequent exposures is immediate and greater than the initial exposure provoked.  B-cells when latently infected with EBV make heterophile antibodies, and when actively infected are killed by T-cells.
--BASOPHILS are WBC's in the blood that stain blue and are the least common. After they migrate into the tissue they are called MAST CELLS. Basophils are granulocytes with granules containing histamine, heparin and serotonin. They have high affinity receptors for IgE antibodies. When they are activated and release the contents of their granules they cause a type I hypersensitivity rxn, aka: allergic response.
--B220 on B cell makes IgM, D, G, E, A, evolved with T cells (same as CD-45)
--bone marrow is where hematopoiesis takes place after birth, producing precursors to WBC's and RBC's. B-cells develop in the bone marrow.
--CELL MEDIATED IMMUNITY refers to response by macrophages, helper T-cells, NK cells and Killer-T cells.
--CD1 is on almost all cells, definitely all epithelium, presents fats and sugars so T cells can respond to non-proteins
--CD3 is next to TCR on T cells, is phosphorylated when T cell hits MHC

--CD4 on "helper" T cells
--CD4+CD25+ = active Treg, suppress T cells via
--CD4 and CD8 T cells in the gut both make TGFβ
--CD4 Th1 cells activate infected macrophages, help B cells make Ab's, target microbes that persist in macrophage vesicles (mycobacteria, Listeria, Leishmania, donovani, Penumocystis carinii) and extracellular bacteria
--CD4 Th2 cells help B cells make Ab, esp IgE to target helminth parasites
--CD4 Th17 cells ENHANCE NETROPHIL RESPONSE and target extracellular bacteria (Salmonella)
--CD4 T lymphocyte numbers in lungs decreased by bromelain. 6mg/kg bromelain in mice-->decr bronchiolar leukocytes found on lavage, decr EOS, IL-4, IL-12, IL-17, and IFN-α
--CD4 Treg cells suppress T cell responses

--CD5 is an ancient B cell, located in mucosal tissue, makes IgM only
--CD8 "killer" or cytotoxic T cells kill virus-infected cells (flu, rabies, vaccinia) and some intracellular bacteria (use perforin)
--CD8's <-- activated by Th1 CD4's via cytokine ( ??? name it )
--CD34 is on all stem cells that will become immune cells
--CD40 is costimulatory
--CD40L = matches costimulatory on T cell, switches B cells to next class
--CD45 marks regular B cell that makes all kinds of antibodies
--CD80 is a costimulatory signal
--CD86 is costimulatory, the biggie that you find on APC's
--COMPLEMENT = twenty proteins made by liver that serve as part of innate defense system. Can lyse cells, induce inflammation, opsonize cells to enhance phagocytosis. Two pathways must be activated sequentially for full expression. The alternative complement pathway is most imp during initial exposure, because it is not dependent on IgG for activation as the classic pathway is. Both pathways produce C3b which opsonizes foreign material and leads to the formation of the MAC (membrane attack complex).
--DC = dendritic cell
--DENDRITIC CELLS have receptors in common with macrophages (Ig, Fc, C3) and are found in skin (Langerhans cells), lymphoid tissues (esp gut) and lymphatics. They are professional antigen presenting cells (APC's) and help activate T-cells. They are the reservoir for HIV when a patient appears to be in remission.
--EOSINOPHILS = EOS = granulocytes with red staining granules. They are designed to attack invading parasites (nematodes) but also participate in allergic asthma. Their granules contain peroxidase to digest parasites, histaminase to regulate hypersensitivity rxns, and leukotrienes and eosinophil peroxidases to enhance the inflammatory response. EOS attach to nematodes when they are covered with Abs or complement, then suicide by degranulating to hurt the nematode. EOS can phagocytize, but do not present antigen.
--Fc alpha is anti-inflam
--FCD = follicular dendritic cell, not related to dendritic cell
--GM-CSF = granulocyte monocyte colony stimulating factor, granulocyte proliferation, mast cells, macrophages. Low in pts who are about to convert to Alzheimers, along with IL-6 and IL-10.
--GM-CSF release induced by Schisandra chinensis, also induces IL-8.
--HLA = human leukocyte antigen, a group of alloantigenic proteins, MHC codes for them, certain ones are markers for disease incl DM
--HLA-B27 is present mainly in people with ankylosing spondylitis, Reiter's syndrome aka reactive arthritis, and psoriasis pts with pitted nails (not all psoriasis are HLA-B27 positive).

--INTERFERONS = alpha, beta and gamma. All are antiviral, minor pyrogens, can up-regulate HLA molecules and increase production of other cytokines.
--IFN-α = IFN alpha = made by leukocytes. IFN alpha and beta are secreted by many lymphocytic cell types including NKs, T and B cells, as well as macrophages, fibroblasts, endothelial cells and osteoblasts. Both stim NKs, macrophages and T cells to fight infx or tumors. The interferons also cause most host sx including myalgias, arthralgias, fever, sore throat and headache. IFN alpha is used as a drug treatment for Hep C.
--IFN-α increased by high fat meals (along with IL-6, TNF-α, IL-1β, IL-10, IFN-γ, IL-12 and MIP-1β)
--IFN-α decreased by bromelain. 6mg/kg bromelain in mice-->decr bronchiolar leukocytes found on lavage, decr EOS, IL-4, IL-12, IL-17, and IFN-α, results confirmed earlier findings (intraperitoneal admin of bromelain-->decr CD4 T-lymphs)

--IFNβ = Interferon beta = made by fibroblasts.
--IFNβ -- RX IFNbeta for relapsing multiple sclerosis

--IFNγ = Interferon gamma (IFNg) = made by T-cells.
--IFNγ -- RX used for chronic granulomatous diseases.
--IFNγ reported to increase intestinal permeability and blood-brain permeability
--IFNγ --> most important activator of macrophage phagocytosis, pro-inflam
--IFNγ --> Th1 response to bacteria, viruses, cancer
--IFNγ --> decreases IL-4, increases macrophages, ROS, phagocytosis
--IFNγ --> B cells class switch to IgG
--IFNγ --> Activates CD8 T cells, increases perforin & granzyme production
--IFNγ -- Influences leukocytes in celiac disease, along with IL-18.
--IFNγ -- Coriolous versicolor-->brief upregulation of IFN-gamma and IL-18 (up at 24h, not at 48 or 72hr)
--IFN gamma -- increased by high fat meals along with IL-6, TNF-α, IL-1β, IFN-α, IL-10, IL-12 and MIP-1β

--IgA -- <-- Th3
--IgA = mucosal immunoglobulin present in secretions including saliva, tears, breast milk, GI mucous, prostatic fluid. Helps prevent microbes from attaching to mucous membranes of body. Secreted as a dimer.
--IgA = Primary source of specific immunity for infant while breast feeding.
--IgA -- some people are IgA non-secretors, levels chronically low
--IgD -- Expressed on the surface of mature B cells, human immunoglobulin D (IgD) works with IgM in B cell development. IgD is found in very low levels in serum and does not activate complement.
--IgE <-- Th2
--IgE binds basophils/mast cells and helps defend against parasites. Elevated in allergic or anaphylactic response. IgE is mostly found fixed in the tissues on mast cells bearing the (high affinity) Fce receptor, whether or not antigen is present.
--IgG <-- Th1
--IgG = most abundant circulating Ab. Signals phagocytic cells and helps complement bind antigen. This is the only antibody that can cross the placenta to a fetus. IgG can only activate complement through part 3.
--IgM = the first antibody produced in an acute inflammatory response. Is bound to B-cell surface as monomer, but after that is bound the B cell turned plasma cell can secrete pentamer from of IgM, which can fully activate the complement system because it has ten antigen binding sites.
--INTERLEUKINS = IL = cell signals
--IL-1 --> fever, sleepiness, proinflam with IL-6, made by macrophages, stims APCs, T-cells, B cell Ig prod. Also involved in acute phase response in liver, activation of phagocytes, fever, hematopoiesis.
--IL-1 is good for acute infx and leads to depression if there's no infx to fix.
--IL-1β is the leader of the major pyrogens which also include IL6 and TNFa which is mediated by IL1 release.
--IL-1β, IL-6, IL-21 and IL-17, TNF-α expression in mice reduced by treatment with ursolic acid

--IL-1 <--adipose, resistin
--IL-1 aka osteoclast activating factor, provoked by PTH binding ostoblast in bone
--IL-1 in bone-->osteoclast breaks down bone to maintain blood Ca+
--IL-1 production in bone limited by est in females, testosterone in males
--IL-1 and IL-6 provoke sequestration of ferritin into macrophages (IL6 strongest)
post-menopausal osteoporosis caused by low est-->high IL-1-->osteoclasts eat bone
--IL-1 production increased by Cordyceps sinensis, also incr TNFa, NK activity, T cell numbers, and lymphocyte lifetime
--IL-1 beta increased by Sambuca, suppressed by Withania, increased by high fat meals along with IL-6, TNF-α, IFN-α, IL-10, IFN-γ, IL-12 and MIP-1β
--IL-2 --> proliferation of T cells, all kinds including naive, B cells switch to IgM, produced by activated helper T cells to stim more T's, NK killing and Ab production by B cells.
--Celiac risk variants in the 4q27 region harboring IL2 and IL21 genes.
--IL-2 is a key cytokine for T-cell activation and proliferation. Along with IL-21 is implicated in the mechanism of celiac and other autoimmune conditions, namely type 1 diabetes and rheumatoid arthritis, suggesting that the 4q27 region might represent a general autoimmune disease risk locus.
--IL-2 Coriolus versicolor upregs production of IL-2 and IL-12
--IL-3 helps trigger Mast cell development and maturation, along with stem cell factor, IL4 and IL9.
--IL-4 --> Th2 --> IL-4, 5, 10, 13, B cells heavy chain splicing and class switch to IgE, lowers IFNγ
--IL-4 inhibits Th3 response
--IL-4 and IL-13 enhance Fe uptake and storage
--IL-4 and 5 both promote growth and activation of mast cells and eosinphils
--IL-4, 5, 10 all promote growth and differentiation of B-cells
--IL-4 helps trigger Mast cell development and maturation, along with stem cell factor, IL3, and Th2 cytokines such as IL9.
--IL-4 decreased by bromelain: 6mg/kg bromelain in mice-->decr bronchiolar leukocytes found on lavage, decr EOS, IL-4, IL-12, IL-17, and IFN-α, results confirmed earlier findings
--IL-4 and IL-6 were undetectable after tx with coriolus extract
--IL-5 is part of Th2 response, sensitizes mast cells, B cells class switch to IgA
--IL-6 is part of Th2 response
--IL-6 is pro-inflam, adipokine, does not inhibit Th3 response, aka B-cell stimulating factor (BSF-2)
--IL-6 --> increased circulation, acute inflammation, osteoblasts say make osteoclasts
--IL-6 --> FEVER. One of the major pyrogens along with interleukin 1β and TNFa which is mediated by IL1.
--IL-6 --> anxiety, increases with panic and stays high longer in females
--IL-6 --> increases cortisol, increased during intense exercise, muscle contraction
--IL-6 --> increased VEGf --> angiogenesis esp in cancer
--IL-6 and IL-1 provoke sequestration of ferritin into macrophages (IL6 strongest)
--IL-6 decreased by: beets, scutellaria, avocado, fish oil, exercise, mindfulness meditation and sleep, estrogen and progesterone inhibit production in umbilical cord blood
--IL-6 increased by: eating a burger, peak is 4 hours later
--IL-6 increased by sambuca (along with increased IL-1 beta, TNF-alpha, IL-8)
--IL-6 elevated in cancer: multiple myeloma and many other cancers, may play a part in cachexia
--IL-6 when elevated-->poor prognosis in cancer, dies faster
--IL-6 low in pts who are about to convert from mild cognitive impairment to Alzheimer's (also IL-10 and G-CSF)
--IL-6 and IL-4 were undetectable after tx with Coriolus versicolor extract
--IL-6 (IL-6, TNF-α, IL-1β, IFN-α, IL-10, IFN-γ, IL-12 and MIP-1β) increased after a high fat meal
--IL-6, IL-21, TNF-α, IL-1β and IL-17 expression in mice reduced by treatment with ursolic acid

--IL-7 <--made by macrophages and DC's
--IL-7 is the default growth cytokine for undifferentiated Th0 proliferation --> IL-2
--IL-8 <-- from adiopose, visfatin
--IL-8 is a chemokine that brings neutrophils especially to adipose tissue (is one of the minor pyrogens)
--IL-8 increased by sambuca, induced by schisandra chinensis along with GM-CSF
--IL-9 helps trigger Mast cell development and maturation, along with stem cell factor, IL3, and Th2 cytokines such as IL4 and IL9.
--IL-10 --> Th3 response, decreases Th1, increases Th2
--IL-10 is produced by some tumors, along with TGF-beta to impair the immune response to them
--IL-10 inhibits the production of IL-2 and TNF in helper T-cells to favor a humoral immune response over a cell mediated one, so favors a cell mediated response
--IL-10 is low in patients who are about to convert from mild cognitive impairment to Alzheimer's, along with IL-6 and G-CSF.
--IL-10 increased by high fat meals (along with IL-6, TNF-α, IL-1β, IFN-α, IFN-γ, IL-12 and MIP-1β)
--IL-12 produced by monocytes and B cells, induces IFN gamma production by T and NK cells, enhances their cytotoxicity
--IL-12 --> activates Th1 --> IFNgamma, GM-CSF, TNFalpha, IL-2, more IL-12,
--IL-12 --> B cells class switch to IgG
--IL-12 <-- decreased by stress
--IL-12 <-- made by DC and macrophages
--IL-12 inhibits Th3 response
--IL-12 incr by high fat meals, also IL-6, TNF-α, IL-1β, IFN-α, IL-10, IFN-γ and MIP-1β
--IL-12 decreased by bromelain: 6mg/kg bromelain in mice-->decr bronchiolar leukocytes found on lavage, decr EOS, IL-4, IL-12, IL-17, and IFN-α, results confirmed earlier findings (intraperitoneal admin of bromelain-->decr CD4 T-lymphs)

--IL-12p40 -- Withania/Ashwagandha extract shown to significantly suppress lipopolysaccharide-induced production of proinflammatory cytokines TNF-alpha, IL-1beta and IL-12p40, but had no effect on IL-6 production at the protein and transcript level
--IL-13 is part of Th2 response and causes mucus production
--IL-13 and IL-4 enhance Fe uptake and storage
--IL-15 = anti-inflammatory cytokine, preserves glutathione
--IL-15 - present more in gut
--IL-15 incr by dietary leucine
--IL-15 signals mTOR (Mammalian Target of Rapamycin) mechanism-->prot & mm manufacture. Linked to mitochondrial biogenesis, incr thermogensis, and incr energy utilization efficiency prob via activation of the longevity gene SIRT-1.
--IL-15 - a myokine, augmented by exercise, levels in skin are 50% higher after exercise
--IL-17 --> activates Th17 -->more IL-17, but NOT IL-4 or IFNγ
--IL-17 --> stimulates neutrophils, regulates chemokine production
--IL-17 decreased by bromelain: 6mg/kg bromelain in mice-->decr bronchiolar leukocytes found on lavage, decr EOS, IL-4, IL-12, IL-17, and IFN-α, results confirmed earlier findings (intraperitoneal admin of bromelain-->decr CD4 T-lymphs)
--IL-17 expression in mice reduced by treatment with ursolic acid (also TNF-α, IL-1β, IL-6, IL-21)

--IL-18 = Pro-inflammatory. Influences leukocytes in celiac disease, along with IFN-gamma. Reduced by Ganoderma, which is used in RA.
--IL-18 Coriolous versicolor-->brief upregulation of IFN-gamma and IL-18 (up at 24h, not at 48 or 72hr)
--IL-21 = T-cell derived cytokine (same as IL-2), enhances B-cell, T-cell and NK-cell proliferation and interferon-gamma production. Along with IL-2 is implicated in the mechanism of celiac and other autoimmune conditions, namely type 1 diabetes and rheumatoid arthritis, suggesting that the 4q27 region might represent a general autoimmune disease risk locus.
--IL-21 is implicated (along with IL-2) in the mechanism of celiac, DM1 and RA
--IL-21, TNF-α, IL-1β, IL-6 and IL-17 expression in mice reduced by treatment with ursolic acid

--IL-22 production is stimulated by gut bacteria of the genus Clostridia, resulting in decreased permeability of the intestinal lining and a decrease in dietary allergens entering the bloodstream.
--IL-23-->division of Th17 (fungus can increase production of IL-23 in place of IL-12)
--IL-23, (TGFβ, IL-6) --> Th17
--LYMPHOCYTES = increased in blood with acute viral infection, PMNs are reduced. CTLs and NKs are involved in killing virally infected cells. IFN from T-cells helps inhibit viral replication. Lymphocytes live longer with Cordyceps.
--MACROPHAGES are cells that phagocytize bacteria/viruses/other antigens that have been opsonized. Macrophages are APC's. They also break down the ingested material and present antigen to T-helper (CD-4) cells. --
--Macrophages also make IL-1 and TNF to induce CD-4 T-cell function and activity.
--Macrophages are Decreased in the kidneys by modified citrus pectin, in Increased in the peritoneum by Astragalus.
--Macrophages flood to the site of insulin injections and hang around in adipose tissue http://www.medpagetoday.com/Endocrinology/Diabetes/43315?xid=nl_mpt_DHE_2013-12-10

--MAST CELLS once were basophils. They line body surfaces and alert the immune system to local infections. In allergy they react to innocuous antigens that are not associated with pathogens. Their granules contain histamine, heparin and serotonin. They have high affinity receptors for IgE antibodies. When they are activated and release the contents of their granules they can cause a type I hypersensitivity rxn, aka: allergic response, and they can attract T cells causing a type IV delayed hypersensitivity rxn. When activated they release granules, synthesize prostaglandins, leukotrienes, and cytokines. Can cause life threatening circulatory collapse (anaphylaxis). The immediate allergic rxn caused by mast-cell degranulation is followed by a more sustained inflammation known as the late-phase response, involves recruitement of other effector cells esp Th2 lymphocytes, eosinophiles and basophils. Mast cells mature locally, and their development is triggered by stem cell factor, IL3, and Th2 cytokines such as IL4 and IL9.

--MEGAKAROYCYTES are the myeloid cells that fling off bits of themselves to make PLATELETS.
--MHC = major histocompatibility complexes, I and II, are a cluster of gtenes that code for HLA. Each person inherits two sets of MHC from mom and dad each, for a total of four sets of co-dominant genes. HLA molecules are where antigens are offered (presented) to the immune system. Zwickey calls them hot dog buns. Antigens must attach to one of the two types to stimulate T-cell activity. Class I (HLA-A, B, C) are on all nucleated cells anre are important in CTL recognition of self vs non-self. Class II MHC (HLA-DQ, DP, et) are on specific cells such as machrophages, dendritic cells and Langerhan's cells (on APC's)

--MIP-1β -- increased by high fat meals along with IL-6, TNF-α, IL-1β, IFN-α, IL-10, IFN-γ, IL-12

--MONOCYTES = the cells that become MACROPHAGES after they have migrated into the tissue. Monos are the biggest cells seen on a peripheral blood smear. Increased in circulation with chronic bacterial infections.
--NATURAL KILLER CELLS = large granular lymphocytes that are part of innate or nonspecific immunity. Increased by playing the drums! Not MHC class restricted like T cells are. They can attack tumor cells and virally infected cells that have down-regulated their MHC class I molecules. NK's secrete cytotoxins and induce apoptosis of target cells after binding. They have no mechanism for memory. They are found in high numbers in the interstitial space of the lung, intestinal mucosa, and liver. Activity of NK cells is stimulated by drumming and Cordyceps sinensis.
--NEUTROPHILS = PMNS = polymorphonuclear cells = the first line of defense, these cells hang out in blood vessels and break loose to float toward sites of infection when they receive a chemotactic signal. They do not present antigen, but that are phagocytotic. They are the most common of granulocyes, so have granules = lysozomes containing digestive enzymes and bacteriocidal oxidants. Neutrophils can adhere to the lining of venules and secrete things that help them get through the membrane and into the tissue where they fight infection.
--NFKbeta lowered by olive oil, fish oil quercetin, vitamin c, Glycyrrhiza
--NFKbeta when lowered, in turn lowers TNFalpha
--NFKB increased in obesity and metabolic syndrome, decreased by weight loss, increased acutely after a high carb high sugar meal even in a lean person
--NFKbeta is the gate keeper, leads to invasiveness in cancer, stops apoptosis, increases cell division
--NFKb --> incr TNFalpha, IL-6, angiogenesis
--NFKB transcription is upregulated by stress, high cortisol, and once these genes are turn on they can stay turned on for years
--NF-kB molecule = a transcription factor, controls the transcription of DNA for the perpetuation of the inflammatory immune response. Acts as a switch to turn inflammation on and off. Detect noxious stimuli (infx, free radicals, cellular injuries)-->directs DNA to produce inflammatory cytokines
NF-kB proteins localized in the cytoplasm, associated with a family of inhibitory proteins known as inhibitor of kB (IkB). IkB prots normally bound to NF-kB and block their nuclear localization signal. Provoking stimuli can degrade IkB-->nuclear translocation of NF-kB to be free to activate DNA synthesis of inflammatory cytokineS.
--PEYER'S PATCHES are groups of mucosal-associated lymphoid tissue (MALT) in the intestinal epithelium. Full of lymphocytes, plasma cells (B-cells that are making IgA antibodies for secretions) and macrophages.
--PGE2 = prostaglandin E2, the most inflammatory, used in Th2 responds
--PGE2 inhibits Th1 response when high
--PGE2 lowered by: Glycyrrhiza
--SPLEEN is organ made of reticular fibers which removes old blood cells (red and white) and pathogens from the blood. Full of macrophages and lymphocytes.
--Stem cell factor helps trigger Mast cell development and maturation, along with IL3, IL4 and IL9.
--T-cell precursors begin in liver of fetuses and in bone marrow of born people, and go via blood to the thymus to undergo selection and mature. T-cells can be helper-T's (CD-4) or killer T's (CD-8). T-cells regulate immunse responses and are most of the cell-mediated immune response, with the help of macrophages. T-cells are activated when an APC presents a recognizable antigen along with the proper MHC molecule and cytokines. Helper T's respond to antigent presented in MHC class II molecules. When activated, helpers secrete cytokines that promote proliferation, maturation and activation of T cells na dother T cells, plus memory cells of B or T cell origin. Killer T's are also known as CTL's (cytotoxic T lymphocytes). Killer T's respond to MHC class I molecule antigen presentation and specialize in killing virally infected self-cells and cancer cells. Suppressor T-cells (CD-17??) are proposed to suppress or terminate immune responses and they may or may not exist. Cordyceps increases T cell numbers.
--CTL = cytotoxic T lymphocyte == killer T cell = CD-8 T cell, see T-cell
--TGFβ --> activates Th3 --> IL-10, CD4+CD25+ Th3 cells, IL-2, →IgA class switch, inhibits B cell and macrophage growth
--TGFβ --> B cells class switch to IgA
--TGFβ in the gut made by both CD4 and CD8 T cells
--TGFβ enhances differentiation of other Th3 cells
--TGFβ downregulates production of IL-12 by DCs and macrophages (downreg Th1)
--TGFβ, IL-6, IL-23 --> Th17
--TNF alpha = made by macrophages to activate helper T cells, can induce necrotic death of tumor cells in animals. At low concentrations it incrases synthesis of adhesion mols in endothelial cells so PMNs can attach and escape BVs. At high concentrations it plays a role in endotoxin-induced septic shock and cachexia by inhibiting the utilization of fatty acids.
--TNF alpha -- functions to contain of local infx, prevents spread to other organs
--TNF alpha is dysfx once infx is in blood (septicemia), causing DIC (systemic clotting) which consumes all clotting proteins-->pt to looses ability to clot-->failure of vital organs, high mortality rate
--TNFa elevation-->angry and hostile, IL6-->anxious and depressed, IL1-->malaise (Zwickey)
--TNA alpha -- too much causes leaky gut, Crohn's, UColitis (IgG vs enteric microbes, colon too acidic)
--TNF-α (esp IL-1b) can stim matrix metalloproteinases to break down extracellular collagen matrix (hallmark of inflam joint dz)
--TNF alpha -- pyrogen induced by IL1
--TNF alpha --> increase macrophage ROS, brings in lymphocytes, macs, eos basos
--TNF alpha -- burn victims make so much they don't get cancer
--TNF alpha <-- made by macrophages and DC's, adipose too, part of Th1 response
--TNF alpha increased by Sambuca (elderberry), Cordyceps sinensis (Cordyceps also incr IL-1, NK activity, T cell numbers, and lymphocyte lifetime)
--TNF alpha induced by lipopolysaccharide, and suppressed by Withania/Ashwagandha extract, and high fat meals (IL-6, TNF-α, IL-1β, IFN-α, IL-10, IFN-γ, IL-12 and MIP-1β all incr by high fat meals)
--TNF alpha: lower by lowering NFKbeta, use olive oil, fish oil, quercetin, eat beets
--TNF alpha inhib: Artemisia absinthium, Tripterygium wilfordii (toxic), Taraxacum, Zingiber, Rosmarinus, Glycyrrhiza
--TNF-α in mice inhibited by treatment with ursolic acid (also IL-1β, IL-6, IL-21 and IL-17)

--Th0 = naive
--Th1 --> IFNγ, GM-CSF, TNFalpha, IL-2, more IL-12, class switch to IgG. Increased by: astragalus.
--Th2 --> IL-4, 5, 10, 13, class switch to IgE-->eos & mast degranulation, diarrhea
--Th3 --> IL-10, CD4+CD25+ Th3 cells, IL-2, →IgA class switch, inhibits B cell and macrophage growth
--Th17 <-- HIV pts are deficient in these cells
--Th17 -->more IL-17, but NOT IL-4 or IFNg (inhibited by IL-4, 12)(OK with IL-6 and TGFb)
--Th17 express receptors for IL-23-->increased division
--Th17 --> stimulates neutrophils, regulates chemokine production (HIV patients are deficient in Th17 cells)
--Th17 --> IL-17, IL-6 --> acute inflammation, autoimmunity: Rheumatoid arthritis et al
--Th17 -- Ursolic acid ameliorates autoimmune arthritis via suppression of Th17 and B cell differentiation. Ursolic acid (UA) treatment significantly reduced the incidence and severity of collagen-induced arthritis in mice. Decreased expression of proinflammatory cytokines (TNF-α, IL-1β, IL-6, IL-21 and IL-17) and oxidative stress markers (nitrotyrosine and iNOS) in arthritic joints. Significantly decreased the number of Th17 cells, increased the number of Treg cells in the spleens. Significantly reduced the serum CII-specific IgG levels in CIA mice. Confirmed in an in vitro model of Th17 differentiation. Dose-dependently suppression of expression of B cell-associated markers Bcl-6, Blimp1 and AID mRNAs in purified CD19+ B cells pretreated with IL-21 or LPS in vitro.

--THYMUS = gland where T-cells mature and those which are specific for self are destroyed by anergy (selection). Epithelial cells of the thymus secrete growth factors which up-regulate CD-4 and CD-8 cell formation and help activate T-cells. This gland involutes at puberty, reducing T-cell production.
--TLRs less in gut, some bact in gut don't bind TLR's anymore
--Treg <-- activated by TGFβ ?? Th3 tolerance

Innate immune system
Phagocytes produce them to blood stream, absorbed through circumventricular areas of brain dt reduced filtration of BBB, bind with endothelial receptors on vessel walls or interact with microglia, activating the arachidonic acid pathway-->incr in thermoregulatory set point in the hypothalamus
Major Pyrogens: interleukin 1β, interleukin 6, and TNFa which is mediated by IL1 release
Minor pyrogens: IL8, TNFbeta, macrophage inflammatory protein-α and beta, IFNa, IFNb, IFNg
Effects: elevation of body temperature, provoke liver to make acute phase proteins, mobilize neutrophils from the bone marrow endothelium, mobilize protein and energy from fat and muscle, and TNFa stimulates migration of dendritic cells to lymph nodes, and maturation (initiation of adaptive immune response)


--IL2, IL12, INFgamma: fight infx & cancer via T lymphocytes and PGE3
--stim NK cells
--suppressed by stress, toxins, bad fats, sugar, high PGE2
--to stimulate: (AMRjune 06): avoid stress, bad fats, sugar, eat fish, fish oil, olive oil, hazelnut oil (last 2 better raw), acidophilus, bifidus, high silica foods such as millet, rice, horsetail, and DETOX

--IL1, IL6, TNFalpha
--uses B lymphocytes and PGE2 to fight spirochetes and parasites
--IL1b contributes to inflam in brain from glutamate pathyway hyperstimulation (brain recovery.com perlmutter)
--antagonists of IL1B and TNFalpha can reverse periodontal dz (AMR June 06)
--to stim TH2: Bupleurum, curcurmin, astragalus, echinacea

--IL10, TGFbeta, sIGA induces tolerance and can suppress TH1
--bifidobacterium-->increase IgA
--VIT A and L-gluatmine--> inc IgA
--lactobaccilli GG-->less allergies in infants (Lancet 2001, 351)
--breast milk/colostrum-->inc sIgA

Vitamin C at 10-15mg/dl in serum aggravates/activates WBC's, anticancer and antiviral effect, impossible to get these levels with oral intake, must be given IV
Vit C downregs NF-kappa B in 35%

Natural anti-inflammatory agents for pain relief.
Maroon JC, Bost JW, Maroon A. Natural anti-inflammatory agents for pain relief. Surg Neurol Int.2010;1:80.

Prostaglandins act as short-lived localized hormones that can be released by any cell of the body during tissue, chemical, or traumatic injury, and can induce fever, inflammation, and pain, once they are present in the intercellular space. Thromboxanes, which are also hormone activators, can regulate blood vessel tone, platelet aggregation, and clot formation to increase the inflammatory response.[92,82] The inflammatory pathway is a complex biochemical pathway which, once stimulated by injury, leads to the production of these and other inflammatory mediators whose initial effect is pain and tissue destruction, followed by healing and recovery.[34,51] A major component of the inflammatory pathway is called the arachidonic acid pathway because arachidonic acid is immediately released from traumatized cellular membranes. Membrane-based arachidonic acid is transformed into prostaglandins and thromboxanes partly through the enzymatic action of cyclooxygenase (COX)[34,57]. There are two types of COX enzymes, COX-1 and COX-2. Both the enzymes act similarly, but selective inhibition (as accomplished by selective COX-2 inhibiting NSAIDs) can make a difference in terms of side effects.

Acetylsalicylic acid works by irreversibly disabling the COX enzymes to block the cascade [Figure 1]. NSAIDs have evolved from blocking both COX-1 and COX-2 to selectively only blocking COX-2 in order to inhibit the inflammatory response and reduce the production of inflammatory prostaglandins and thromboxanes. The major push to develop the selective COX-2 inhibitors has been the recognition of significant complications associated with the nonselective COX-1 and COX-2 NSAIDs. Nonselective NSAIDs’ major side effects include significant gastrointestinal upset, gastritis, ulceration, hemorrhage, and even death. By locking COX-1, which also normally acts to protect the gastrointestinal mucosa, nonselective NSAIDs and aspirin can cause significant gastric tissue damage.[34,51,78,91,3,101,115]
Various studies have also shown that NSAIDs can delay muscle regeneration and may reduce ligament, tendon, and cartilage healing.[4,13,77] Specifically, NSAIDs are believed to wipe out the entire inflammatory mediated proliferative phase of healing associated with WBC actions (days 0–4). A study of the effects of NSAIDs on acute hamstring injuries was done in humans by Reynolds et al.,[93] and these investigators concluded that patients who used NSAIDs did not experience a greater reduction of pain and soft-tissue swelling when compared with the placebo group. Interestingly enough, the authors noted that the NSAIDs’ group had worse pain associated with severe injuries compared with the placebo group.
The NSAIDs are also known to have adverse effects on kidney function.[31] Dehydration or preexisting chronic renal failure or disease, resulting in stimulation of the renin–angiotensin system, may predispose certain populations to acute renal failure through inhibition of prostaglandin synthesis, which can occur when taking NSAIDs.[31] The National Kidney Foundation asserts that approximately 10% of kidney failures per year are directly correlated to substantial overuse of NSAIDs.
Life-threatening side effects of selective COX-2 NSAIDs
in December 1998, celecoxib (Celebrex) was approved by the Food and Drug Administration (FDA) as the first selective COX-2 inhibitor for treatment of arthritis pain.[92,13,22] Rofecoxib (Vioxx) was approved several months later, followed by valdecoxib (Bextra).[92,28,67,79] These NSAIDs were designed to allow continued production of the gastrointestinally protective prostaglandins produced through the COX-1 enzyme system while blocking the COX-2 enzyme that produces the inflammatory prostaglandins.[34,45,51,89]

Celebrex, Vioxx, and Bextra quickly became the mainstay for the treatment of chronic pain conditions related to inflammation.[71] Within a few years, an estimated 15–20 million people in the US were using selective COX-2–inhibiting NSAIDs on a long-term basis. These drugs became the most commonly used pharmaceutical agent with more than 70 million NSAID prescriptions written each year and 30 billion over-the-counter NSAID tablets sold annually. It was estimated that 5–10% of the adult population used NSAIDs, and among the elderly (a group at higher risk of nonselective NSAID-induced gastrointestinal complications), the use of these drugs was as high as 15%. The general acceptance of these drugs was due to the perceived lack of serious gastrointestinal side effects that had been associated with the nonselective class of NSAIDs.[26,119]

On September 30, 2004, Merck Research Laboratories announced the global withdrawal of rofecoxib (Vioxx), its primary selective COX-2–inhibiting NSAID.[52,90,122] Analysis of the results of the Adenomatous Polyps Prevention on Vioxx study (known as the APPROVe study) showed that there was double the risk of serious thromboembolic events, including myocardial infarction, which became apparent after 18 months of Vioxx treatment.[26] Selective COX-2 NSAID’s thrombotic mechanism of action is based on COX-1’s unopposed action to continued platelet synthesis of thromboxane. Thromboxane is a thrombogenic and atherogenic eicosanoid. Prostacyclin prevents formation of platelet clotting. By inhibiting COX-2 that blocks production of prostacyclin (PGI2) there is unopposed thromboxane which will increase the clotting risk. Thus, inhibiting prostacyclin led to the increased risk of thrombotic cardiovascular and cerebrovascular events.[5,26,73,123]
Natural compounds for inflammation

Because of the significant side effect profiles of steroidal and NSAID medications, there is a greater interest in natural compounds, such as dietary supplement and herbal remedies, which have been used for centuries to reduce pain and inflammation.[94] Many of these natural compounds also work by inhibiting the inflammatory pathways in a similar manner as NSAIDs. In addition to the COX pathway, many natural compounds act to inhibit nuclear factor-kB (NF-kB) inflammatory pathways.
NF-kB inflammatory pathways and cytokines

The NF-kB molecule is a transcription factor that controls the transcription of DNA for the perpetuation of the inflammatory immune response. It acts as a switch to turn inflammation on and off in the body. NF-kB has the ability to detect noxious stimuli, such as infectious agents, free radicals, and other cellular injuries, and then directs DNA to produce inflammatory cytokines. The NF-kB proteins are localized in the cytoplasm of the cell and are associated with a family of inhibitory proteins known as inhibitor of kB (IkB).[43,119] The TNF-α, and especially IL-1b, can also directly stimulate enzymes known as matrix metalloproteinases, which break down extracellular collagen matrix, a hallmark of inflammatory joint disease.[32,76,77] The IkB proteins are normally bound to NF-kB and block their nuclear localization signal. A variety of provoking stimuli can degrade the IkB and result in the nuclear translocation of NF-kB to be free to activate DNA synthesis of inflammatory cytokineS.

Aspirin is now believed to target both the NF-kB and COX pathways. These agents inhibit the NF-kB pathway in endothelial cells and block NF-kB activation to inhibit leukocyte recruitment.[114,115,116] NSAIDs have also been found to inhibit both the COX system and the NF-kB pathway. Immunosuppressant drugs also reduce nuclear expression of NF-kB.[39,70,75] Research now indicates that blocking the activation of NF-kB along with other inflammation mediators [Table 2] is the major mechanism for reducing inflammation by natural compounds.

Lectures by Dr Zwickey and Dr Ambrose
Janeway's Immuno Biology 7th Ed

IL-6, IL-10 and G-CSF are all low in pts with Mild Cognitive Impairment

Differential effect of Coriolus versicolor (Yunzhi) extract on cytokine production by murine lymphocytes in vitro.

Clostridia appear to increase IL-22 which decreases gut permeability


Ursolic acid to suppress Th-17 for tx of RA
Acta Pharmacol Sin. 2014 Sep;35(9):1177-87. doi: 10.1038/aps.2014.58. Epub 2014 Aug 4.

High fat meals cause cytokine release
Acta Diabetol. 2014 Sep 3.
High-fat meals induce systemic cytokine release without evidence of endotoxemia-mediated cytokine production from circulating monocytes or myeloid dendritic cells.
Aim of this study: to determine effect of the postprandial milieu on inflammation and the inflammatory response of APC's in DM1 (T1D)
N=11 with DM1 and 11 non diabetic controls
FinnDiane study
Two fatty meals during 1 day
Measured: Cytokine responses in monocytes and myeloid dendritic cells (mDCs), serum lipopolysaccharide, TG's and cytokine concentrations (fasting and postprandial blood)
RESULTS: Postprandially, patients with T1D and controls showed significant increases in eight inflammatory cytokines (IL-6, TNF-α, IL-1β, IFN-α, IL-10, IFN-γ, IL-12 and MIP-1β) without concomitant increase in serum LPS activity. Serum cytokine production was similar in both groups. No postprandial change was seen in the IL-6, TNF-α or IL-1β production of mDCs or monocytes. At fasting, diabetic mDCs exhibited higher LPS-induced IL-6 and IL-1β production than controls.
CONCLUSIONS: MINE: High fat meals make your body feel like dying.
Acute high-fat meals increase circulating cytokines but have no effect on serum lipopolysaccharide activity levels or cytokine production in circulating mDCs or monocytes. Our results suggest that postprandial increase in serum cytokine levels is neither mediated by circulating endotoxins nor the activation of circulating innate cells. The production of high-fat meal-induced inflammatory markers is most likely regulated at the tissue level.

and many many more that aren't recorded



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