Understand 2nd year medicine

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Inflammation

Mechanisms of autoimmune
- Molecular mimicry - resemblance between host and pathogen antigen: e.g. Multiple sclerosis
- Epitope spreading: An auto-immune response
is triggered by primary autoantigen. This favors the development of Th1. It damages target tissue and releases more autoantigens (Ag2, Ag3, etc.) and hence damage - spread of specificity and chronicity of the disease.

- Autoantibodies made elsewhere enters immunological priveleged sites (e.g. MS: MBP specific Th1 enters BBB


Autoimmunity is normally prevented because

  • Central tolerance in thymus and bone marrow:
    • Immature autoreactive T cells (high affinity) undergo apoptosis  
  • Peripheral tolerance:
    • Mature autoreactive T cells do not receive costimuli (e.g. B7 from Antigen presenting cells) - anergy


Autoimmune and T cell subtypes
Th1: MS, Type 1 Diabetes Mellitus (macrophage-related?)
Th2: Allergy, asthma, eczema, hayfever
Th17: IBD Inflammatory bowel diasease


Overview of some autoimmune diseases

- MS Multiple Sclerosis

  • Oligoclonal IgG in CSF (Cerebral spinal fluid)
  • MBP (myelin binding protein) bind to HLADR2 - recognized by T cell
  • + BBB blood brain barrier permeability -> Inflammatory cells to CNS which is immunoprivileaged?

- SLE (systemic lupus erythematosus)
  • Young adult female
  • UV light -> Tissue/DNA dmg -> Epitope spreading?
  • Antinuclear
  • Ig complex -> glomerulonephritis
  • Hematoxylin bodies (aggragated DNA and Ig): Lymphocytes that ingest these bodies are called LE cells
  • - May be systemic: Skin (involved in >75% of the cases.. skin le...) and Renal- If only skin is involved: Discoid Lupus Erthematosus

 

- Goodpasture’s syndrome
  • Autoantibody vs glomerular basement membrane

- Celiac Disease
  • Antiendomyseal IgA, antigliadin IgA, anti-tissue transglutaminase IgA (ALL ARE IgA!)
  • HLADQ2&8

- Rheumatoid arthritis
  • RhF (rheumatoid factor IgM) made by B cells vs Fc portion of IgG antibodies in blood-> immune complex (type 3 hypersensitivity)
  • Activate complement - c5a - chemotactic for WBC to enter joint space
  • Pannus formation (granulation tissue formed by fibroblast and inflammatory cells cell)

- Grave’s disease
  • Anti-TSH receptor antibody
  • F3:1M

- Hashimoto thyroiditis
  • Delayed type hypersensitivity: Th1 destroy parenchyma (initial thyrotoxicosis and later hypothyroidism) - type 4 hypersensitivity
  • IgG autoantibody blocks TSH receptor - decrease hormone synthesis - type 2 hypersensitivity
  • Antimicrosomal and thyroglobulin antibody

- Myasthenia gravis
  • Autoantibody vs AchR


- IBD  Inflammatory bowel disease

NOD2 mutation in Crohn’s disease

  • NOD signalling
    1. NOD2 binds to muramyl dipeptide (MDP), intracellular signalling cascade activates RICK. The RICK, NOD2, MDP  complex allows ubiquination of IKB. IKB is degraded allowing the originally-bound NFkB to translocate to nucleus and promote transcription of cytokines (both antiinflammatory and proinflammatory) and defensins.
      • Antiinflammatory: Defensins (antibiotic) and antiinflammatory cytokines IL10  made
      • Proinflammatory: TNF-alpha, IL2 and IL8
  • In NOD2 mutations, the signalling causes proinflammatory to outweigh the anti-inflammatory.
  • Treatment: TNF-alpha inhibitors e.g. Infliximab


  • Types of Hypersensitivity (ACID)
    1: IgE: Mast cell and Th2 (involves antibody production! & ALLERGIES!!!)
    • (Sensitizing dose) First exposure -> APC ingest and present peptide as MHCII -> Present to Th2 -> Th2 produce IL4 and IL5
      • B cell: Memory cell and plasma cell that makes IgE (fx of IL4)  -> IgE becomes bound to mast cell (muscle/TISSUE) /basophil (blood)
      • IL5 stimulates eosinophil to rid parasite
    • (Anaphylactic dose) Second exposure: TWO OR MORE IgE x Allergen -> Degranulation (e.g. histamine)

    http://journals.prous.com/journals/dot/19983411/html/dt340957/images/Bha1.gif

    • E.g. Allergic rhinitis (hay fever), allergic rhinoconjunctivitis, asthma, eczema (atopic dermatitis), dietary
      • Air allergen -> Resp. tract (mucosal edema, hypersecretion)
      • Food allergen -> GI tract (ab. pain, nausea, vomitting and diarhoea to rid antigen)
      • If directly to blood - e.g. penicillin -> immediate systemic anaphylactic shock
    2: IgM&G: Cytotoxicity - tissue specific autoantibody (Type 2: 2 Ig’s involved)
    • Hemolytic anemia: Antibodies against protein antigen on RBC → Macrophage engulf because FcR → Hemolytic
      • *** RhD antigen not autosomal/recessive just +/- (85% of population is RhD+)
        • Rh disease: If mom is RhD - and dad is RhD + -> Fetus may be RhD+
        • First pregnancy: Fetal RBC not crossed... therefore no IgM/G made... until placenta separates that is! When it is separated, it enters maternal bloodstream and makes the IgM/G.
        • Second pregnancy and if fetus is RhD+: IgG (IgM can’t cross placenta) crosses placenta and fixes complement causing hemolytic anemia of baby
          • RhD RBC x Autoantibody complex (Fc) engulfed by RES of spleen and liver (Kupffer cells of liver or macrophage in spleen containing FcR)  - warm AIHA
        • Treatment for mother: Anti-Rh IgD antibody clears the RhD+ RBC cell of fetus before Mom gets sensitized and make IgG
    • Grave’s disease: Thyroid -  vs TSH receptor  -> + TSHR signalling and + T3/4 production
    • Good pasture: Non-collagenous protein on GBM (nephritis) and alveoli (lung hemorrhage)
    • Myesthenia gravis - Antagonist at AChR - skeletal muscle weakness
    • Pernicious Anemia: Antibodies react against intrinsic factor --> B12 can't find
    • Rheumatic heart disease: Antibodies made against strep antigen cross react with antigens in heart -> Neutrophil and macrophage -> Chronic ainflammation
    3: IgG: Immune complex (many... most common IgG!)
    • Larger complexes cleared faster than small complex
    • High Ab-Ag affinity
    • Activate complement
    • Systemic
    • Complement activation
    • e.g. SLE, RA
    4: Type 4: Th1 cell mediated (macrophage............)
    • DTH (reaction takes 2-3 days)
      1. APC’s MHCI x Th1’s TcR
      2. Th1 release IFN-gamma
      3. IFN-gamma stimulates macrophage
      4. Macrophage cause damage!!! - Secrete growth factors that cause fibrosis and granulomatous
    • Monocytes and lymphocytes
    • Germinal centers!
    • e.g. TB, type 1DM, MS, Hashimoto’s thyroiditis, Crohns


    Viral hepaitits: MHC1 x CD8+ -> Cytotoxic T cell -> Kill infected hepatocyte (if chronic - cirrhosis)
    PPD Test for TB


    purified protein derivative (PPD) of M. tuberculosis is injected intradermally into the flexor surface of the forearm

    The interpretation of tuberculin tests depends on BCG vaccination history and immune status. For example, in HIV-positive patients, a negative tuberculin test does not exclude TB tuberculosis as it may be due to general anergy.

    The greater the reaction, the more likely it is that an individual is infected or has active TB disease

    Diameter of indurationPositivity (degree of hypersensitivity to tuberculin protein)interpretation
    Less than 6 mmNegative – (no significant hypersensitivity to tuberculin protein)
    • Suggests no TB infection but beware false negatives (e.g. HIV, steroid users)
    6 - 15 mmPositive – (hypersensitive to tuberculin protein)maybe....
    15 mm and aboveStrongly positive – (strongly hypersensitive to tuberculin protein)
    • Suggests TB infection or disease.

    Systemic lupus erythematous: type 2 AND 3 hypersensitivity
    - 10F:1M
    - Black and Asian
    - Drug-induced (Mnemonic SHIPP- sulfonamide- hydralizine- isoniazid- phenytoin- procainamid)
    • Antihistone antibody
    - EBV virus molecular mimicry

    - IgM and IgG binds to antigens of cells -> damage and cause hemolytic anemia, leukopenia, thrombocytopenia  (Type 2 hypersensitivity - RBC, WBC, platelet - antiphospholipid antibody) and SPLENOMEGALY
    - IgG Autoantibody binds to cell surface -> Cell destruction -> Cellular antigens released -> 1 Many (Antigen to IgGs) -> form Immune complex (Type 3 hypersensitivity )

     

     - Systemic autoimmune

    • Affected in the order of: Joints> Kidney>Lung>CNS
    • Kidney: Thickened BM, IgG&M and protein deposits - glomerulonephritis (lupus nephritis)
    • Joint: Deposits - myalgia, arthritis - present in 90% of cases resembling RA but no pannus
    • CNS: Thrombosis secondary to complex of Antiphospholipid antibody v.s. platelet -> Stroke
    • Serosal inflammation - pleuritis and pericarditis 
    • Blood vessels - vasculitis
    • Skin: Discoid

    Non-specific symptoms
    - Malaise
    - Weight loss
    - Fever


    http://www.becomehealthynow.com/images/organs/lymphatic_immune/10c.gif

    Lab findings
    - Raised ESR, CRP
    - Leukopenia, thrombocytopenia
    - Normochromic normocytic anemia
    - ANA (the reason why SLE is SYSTEMIC is because nuclear components are found in ALL CELLS!!!)

    • Anti-dsDNA
    • Anti-Ro, Anti-Sm (RNA)
    • Anti-phospholipid (e.g. vs Cardiolipin: A lipid found in inner mitochondrial membran)
      • Antiphospholipid syndrome: Recurrent thrombosis and spontaneous abortions
    • Anti-histones in drug-induced
    - Anti-RBC (hemolytic anemia type 2 hypersensitivity)
    - High gamma-globulin (Igs)
    - Low serum complement (all used up by IgM/Gs for complement fixation!)

    Histology
    - Hyperpigmentation: Lymphocytes damage melanocytes -> Melanin released and enguled by skin macrophage

    Treatment
    - NSAID: COX inhibitor, inhibit NFKB (a dimer of p50xp65: a TF for pro-inflammatory cytokines)
    - Corticosteroid: Inhibits NFKB by increasing TF for IKB (dimerizes with NFKB to inhibit its transcription activity)
    - Antimalarials for skin rash: Inhibit IL1&6 cytokine

    NFKB signalling pathway

    http://www.stat.rice.edu/~siefert/Research/NfKappaB_files/nsp-nfkb-2.jpg

    Inactive: NFKB in cytosol is complexed with IKB (inhibitor).

    When signalling molecule (e.g. TLR, TNF-alpha) binds to receptor, IKB kinase (IKK) is activated and phosphorylates (ubiquinates) IKB for proteosomal destruction and freeing NFKB. Thus NFKB can now translocate to the nucleus where it binds to RE (response elements) of the DNA.

    Note: Ikb can also be ubiquinated by RICK x NOD x MDP (as in Celiac disease)


    Immune system and glomerular damage
    - In-situ immune complex
    1. Circulating antigen trapped in glomerulus BM
    2. Circulating antibody binds to antigen
    3. Immune complex formed in situ
    - Circulating immune complex nephritis
    1. Complex in blood trapped between BM and mesangium
    Lumpy-bumpy appearance of glomeruli because of immune complex deposits!
    1. Autoantibody vs GBM (e.g. Goodpasture’s synderome - Ab vs type 4 collagen in kidney and lung)




    Allergy
    Excessive inflammation in response to allergen (antigen)

    Key point: Th2 mediated; Sensitization: Allergen peptide presented as MHCII on APCto Th2 -> Th2 produce IL4 (B cell plasma cell IgE) and IL5 (eosinophil), Anaphylactic:  2IgE on mast cell x allergen -> mast cell degranulation

    Allergen to MHCII on APC to naive CD4+T cell.
    Acute: APC produces IL4&10 -> CD4+T differentiate to Th2
    Chronic: APC produces IL12 -> CD4+T differentiate to Th1



    Dermatitis
    - Exogenous: Contact
    - Endogenous: Atopic (eczema), s
    eborrheic (scalp and face), discoid (coin lesion on limbs), venous

    Eczema (Atopic dermatitis; atopic = inherited tendency)
    - 20% Child, 5% adult
    Infancy: Hnds and face
    Child: Flexural eczemamatitis
    Adult: Hand der
    - Remission (First 6 months, teen)
    - Triad of usually asthma, eczema and allergic rhinoconjunctivitis
    - Th2 mediated
    - Pathophysiology: IgE vs allergen (e.g. HDM)
    - Risk factors: Stress, sweating (before and after swimming use emollient)
    - Normal skin layers: Stratum corneum, lucidum, granulosum, spinosum (+Langerhan - APC), basalis (+melanocyte)


    http://skinipedia.org/images/photos/melanocyte2.jpg

    The melanocyte in basal layer supplies melanin (in melanosomes) to surrounding keratinocytes. Following exposure to ultraviolet light, there is an increase in the number of melanosomes, their melanin content and their transfer to keratinocytes.

    Pseudopod organelle containing melanin and tyrosinase (tyrosine -> DOPA -> DOPAQUINONE -> DOPACHROME which polymerizes to form melanin)

    Acute eczema
    - Spongiosis: Intercellular edema in keratinocyte; Clinically presented as vesicle
    - Dilated dermal vessel
    - Inf. cell in dermis and epidermis

    Chronic eczema
    - Acanthosis: Thickening of spongiosis
    - Hyperkeratosis: Thickening of corneum
    - Extended Rete ridges
    - Mononuclear cells
    - Dilated dermal vessel

    Investigations for eczema
    - Patient history, family history, distribution of lesion, onset, pets, aggravating factors, sleep disturbance (b/c of itch), effect, previous treatment, growth chart (esp. children)

    Diagnosis
    - Must have itchy skin (pruritis!)
    - At least 3 of the following:

    History of asthma, hayfever

    Flexural eczema

    Dry skin

    Onset in first 2 years of life


    Evidence of infection
    - Weeping
    - Crusting

    http://www.dermis.net/bilder/CD005/550px/img0012.jpg

    - Herpes simplex virus: Small painful blisters fluid
    VERY contageous spread by direct contact - HSV (After primary infection, the virus becomes dormant in ganglia supplying skin. Upon stress/sunlight, it gets reactivated and grows to nerve supplying skin -> Blisters in the dermatome)

    Oral herpes - HSV-1 (1 mouth), Genital herpes - HSV-2 (sex... 2x penetration!)

    Latent viruses
    - HSV herpes simplex virus
    - Varicella zoster (Chickenpox)

    Complication of eczema
    • Growth retardation
    • Bacterial infxn: Staph auereus
    • Viral infxn
      • Eczema herpeticum: Due to lesion therefore prone to HSV1/2 infection - spreads entire body and affect multiple organs - fatal

    http://www.skincarephysicians.com/eczemanet/images/update_article_3.jpg


    Treatment

    Treatment of eczema
    • Emollient / aq. cream for skin and soap substitute: Moisturize and - desire for scratching
    • Topical steroid: Prescribe weakest steroid that is effective (e.g. 1% hydrocortisone) - stronger if thick skin e.g. palm
      • FTU (Fingertip units): 1FTU = 2x Skin area of hand, 4FTU = 8x adult hands
      • Stop using topical steroid once flareup is cleared
      • CONTINUE to use emollient to prevent flareup
      • SFX: Reversible skin thinning, permanent striae, telangiectasia
    • Topical antibiotic
    • Wet wrap

    http://www.aaaai.org/images/photolibrary/wet_wrap_therapy.jpg

    - Antihistamines: H1 receptor antagonist (old ones - sleepy to get you to stop scratching!)

    Contact dermatitis
    - Exogenous dermatitis (NOT ALLERGEN)
    - DISTRIBUTION is key: Earring, shampoo, cosmetic, ring/bracelet (nickel)

    RAST test: Radio allergo sorbent test aka allergy blood testing (adsorb blood’s IgE)
    1. Suspected allergen bound to insoluble material
    2. Patient serum added to
    3. If serum contains IgE vs allergen, it will bind to the allergen
    4. Add radioloabelled anti-IgE Ab (binds to IgE
    5. Unbound is washed
    6. Amount of radioactivity correlates to serum IgE levels

    Prick test (into blood isntant...): Type 1 hypersensitivity (th2 symptoms appear 30 minutes!); INTO skin
    1. Allergen mixed with liquid to make a solution.
    2. A drop of the solution placed on the skin
    3. Skin beneath each drop is pricked with needle to let the soln. seep into skin. (doesn’t hurt)
    4. Skin observed 30 minutes after.

    Patch test: Type 4 hypersensitivity (th1 takes 4 days!), identifies contact dermatitis ONLY; ON skin
    1. Substance on skin applied as patches
    2. 2 days after, the patches are removed and the skin is examined
    3. A further 2 days, the skin is examined again to see if there is any delayed reaction

    http://193.19.159.46/media/images/APPLYINGPATCHES.jpg




    Organ transplant

    Factors that increase graft viability
    • ABO blood group compatibility
    • Absence of preformed antiHLA antibody in recipient (presence of previous exposure to blood product)

    Types of graft
    • Autograft (self to self)
    • Isograft (identical twin)
      • MHC is expressed codominantly
      • Even identical twins express antigenic differences due to somatic hypermutations that occur during their development
    • Allograft (between same species that are genetically different) (allo means other - e.g. allotrope)
    • Xenograft (between 2 different species) xeno means foreign e.g. xenophobe
    Types of rejection
    • Hyperacute rejection: Thrombosis
      • Irreversible
      • Occurs within minutes
      • Involves B cell (antibody) only
        • Type 2 hypersensitivity IgM/G: Recipient’s preformed anti-HLA antibody vs donor’s antigen in vascular endothelium ABO incompatible -> Vessel thrombosis
    • Acute rejection: Inflammation
      • Reversible: Use cyclosporine or tacrolimus (bind to cyclophillin or immunophilin to inhibit calcineurin)
      • Days to weeks
      • Involves T cell  and B cells and others
        • CD8T
          • Perforin
          • Granzyme
          • Fas ligand (CTLLLLL!)
        • CD4T
          • Type 4 hypersensitivity: Host Th1 release IFN-gamma -> Activate macrophage
          • Type 2 hypersensitivity IgM/G: Host Th2 release Il4,5,6 -> B cell to plasma and produce IgM/G -> Vasculitis and intravascular thrombus
        • Macrophage
          • Th1 produce IFN-gamma -> Macrophage produce TNF-alpha to stimulate NK cell
        • NK cell
          • NK cell stimuated - granzyme, perforin!
    • Chronic rejection - irreversible and fibrosis
      • Antibodies immune compelx, cytotoxic cell

    Treatment for organ reject: immunosupression
    • Block cell proliferation e.g. tacrolimus (no IL2!)
    • stop inflammation (e.g. prednisolone)


    Graft versus host disease
    • Bone marrow transplant
    • grafted T cells attack host
    • widespread effects (rash, jaundice, diarrhea, GI hemorrhage)


    Renal replacement therapy: For acute and end-stage chronic kidney failure
    • Conservative
      • Dialysis does not help
      • Many comorbities
      • Symptoms control
        • EPO
        • Vit D analog
        • Dietary control
        • Antimetic
    • Dialysis
      • Acute kidney injury: Uremia (nitrogen-type wastes in the blood), fluid retention causing pulmonary edema, unresponsive hypercalcemia, unresponsive acid-base balance, drug toxicity
      • CKD (Stage 5 - If GFR <10mL/min)
      • Hemodialysis (3x4hrs/ week)
        •  
          • Blood from AV fistula (between vein and artery) to dialysis and back to vein
        • Pump blood through machine where blood is surrounded by dialysate whose concentrations are closely controlled
        • High [] in blood diffuse to dialysate and is removed from blood and vice versa
          • If patient is hypocalcemic: [Dialysate Ca2+] > [Serum Ca2+] so calcium can diffuse into blood
        • Anticoagulant: Heparin
      • Peritoneal dialysis
        • Dialysate in peritoneal cavity
        • Diffusion
        • Convenience: can be done anywhere
    • Transplant
      • Best option for endstage renal failure
      • >90% survival after 1 year
      • Coupled with lifelong immunosuppressant drugs - cyclosporin (Less IL2), azathioprine (Azathioprine -> 6MP -> Inhibit purine synthesis)
        • Higher risk for cancer (e.g. skin)
        • Lifelong screening for cancer



    Summary of GPCRs g protein coupled receptors

    (KISS QUICK til your SIQ of SQS - sick of sex); All B-adrenoceptors are Gs
    alpha1=Q
    alpha2=I
    beta1=S
    beta2=S
    beta3=S
    M1=Q
    M2=I
    M3=Q
    D1=S
    D2=I
    H1=Q
    H2=S
    V1=Q
    V2=S

    Subtypes of GPCR

    • Gq: PLC -> PIP2 to IP3 and DAG; DAG activates PKC whilst IP3 binds to IP3 receptors on calcium channels and ER -> Calcium release
    • Gs: Activate AC -> + cAMP -> +PKA
    • Gi: Inhibits AC -> less cAMP -> less PKA

    Allergy drugs

    Histamine receptors (GPCR!)

    H1: Type 1 hypersensitivity (BV dillation, bronchoconstriction) Gq
    H2: Gastric acid secretion (Histamine made by ECL cells of stomach) Gs

    Antihistamine: H1 receptor antagonist
    - Indication: Allergic rhinitis (hay fever), anaphylactic shock
    - Old sedatives: Sedative sfx, New: No sedative sfx

    Mast cells have high affinity FcR for Fc’s of IgE.

    Upon antigen binding to two IgE on Mast cell / basophil -> degranulate (hates producing leukotriene HPL)
    • Histamine
    • PGD2 (Prostaglandin)
    • LTD4 (Leukotriene)



    Anaphylactic shock
    - Endothelial cell contraction is a reversible process elicited by histamine, bradykinin, leukotrienes
    - Bronchoconstriction due to leukotriene
    - Treated by epinephrine
    • Stimulate reformation of tight junction - decrease permeability therefore -edema +BP
    • Relax constricted bronchial SM

    Immunotherapy: Using IgG so that it can bind to the allergen (no anaphylactic dose as IgE bound to mast cell can not bind to allergen)

    Nasal decongestant
    - Sympathomimetic (mimic effect of sympathetic): Less secretion and Vasoconstriction of nasal vessels -> Less edema
    - Indication: Allergic rhtinitis

    Drugs that cause autommiune response
    - Penicillin covalently binds to surface antigen on RBC -> Creating new epitope -> Macrophage phagocytose and present as MHC to CD4T -> Th2 -> Activate B cells -> Opsonin (IgG bind and is cleared in cicrculation by FcR on phagocytes of spleen) and classical complement activation (IgG and IgM -> MAC)

    Mechanism of penicillin: Mimics substrate for bacterial transpeptidase -> Covalent bond formed between transpeptidase and penicillin -> Transpeptidase enzyme can not function to form the peptide cross links

    Bacterial autolysins breaks peptidoglycan to allow monomers of NAG-NAM-peptide insertion to peptidoglycan. These monomers are then attached via transglycosidase enzymes. Finally, transpeptidase enzymes join the NAM peptide subunits together.

    Vancomycins bind to the peptides of the peptidoglycan monomers and block both the formation of gycosidic bonds and peptide bonds -> weak cell wall and osmotic lysis of the bacterium.

     

     

    Infection



    Capsule: Made of polysaccharide/polypeptide

    • Resist phagocytosis, adhere to mucosal
      • Capsule covers up PAMP/c3b on pathogen so PRR/c3bR on phagocyte can't see


    BUT eventually, IgG antibodies will attach to capsule protein → Fc on IgG x FcR on phagocyte → phagocytosis

    Pili: Shaft (pilin) + adhesive tip (complement to glycoprotein/glycolipid receptor on another cell)

    • Attachment, conjugation (transfer DNA), mobility

    Outer membrane - LPS (endotoxin)

    Vasodilation for inflammation (Anaphylactic, septic) and neurogenic shock
    Vasoconstriction for hypovolemic, cardiogenic

    Quick review of bacteria
    Only in Gram +Only in Gram -
    Cell wall: Thick peptidoglycan, Teichoic acidOuter membrane (LPS, [and its constituents... Lipid A, Polysaccharide)

    Cell wall: Thin peptidoglycan

    Periplasmic space between inner and outer membrane contain enzymes (e.g. B-lactamase) to break down macromolecule






    Superantigen
    - Strep. pyogene
    - Staph. aureus

    Its antigens are presented with MHCII molecules on APC -> POLYclonal Th1 cell stimulation -> IL1, IL6, TNF-alpha release

    Rheumatic fever: Antibody vs heart (endocarditis), joint (RA), kidney (glomerulonephritis)



    Virulence factors: molecules expressed and secreted by pathogens that enable them to achieve the following:



    e.g. bacterial toxin, capsule, hyaluronidase

    Source: Where from
    • contact
    • inhale
    • inoculation (e.g. tattoos - hep C, wounds)

    Route: Endogenous or exogenous
    • endogenous
      • native to body (local commensals getting to wrong place or overgrowth)
    • exogenous
      • not native to body

    Endogenous
    • Candida albican
      • Commensal (host doesn’t benefit, just bacteria does in having a shelter) in oropharyngx, GIT
      • Overgrowth due to imbalance
        • DM: Hyperglycemia → fungal growth
        • Immunosuppressive
        • Thrust, candidiasis

    Exogenous (e.g. Zoonoses - from animals to human)
    • Malaria
      • plasmodium falciparum
      • female mosquito: anopheles
    • Lyme disease
      • deer ticks bite legs
      • borrelia burgorferi


    Adhesion
    • Non-specific: Random
    • Specific: bacterial mediated (bacterail receptor x ligand on cell)
      • Bacteria makes adhesin against glycoprotein on surface
        • Strep. mutans make protein F which targets fibronectin in tooth
    Invasion
    • Make invasin
      • Staphylcocci: Hyalaurinidase → break interstitial bonds between cells
      • Clostridum: Collagenase → to allow RAPID spread of bacteria

    Evasion
    • Block phagocytosis
      • Capsule to prevent immune system e.g. Strep. pneumoniae: Sugar capsule - glistening!
      • Strep. Pyogene: Streptokinase → Activate plasmin  thus fibrinogen to fibrin thus bacteria is coated and can’t be seen by immune system
    • Kill phagocytoes
      • Streptococci release streptolysin to form pores thus lyse phagocytes
    • Survive phagocytosis
      • M. tuberculosis: Endosome membrane changed → no lysosome fuse with endosome
      • Staph. aureus: secrete catalse enzyme → h2o2 to h2o and o2
      • R. rickettii: Secrete PLA2 → Form pores to allow it to escape when lysosome fuses with it (kill and run)


    EndotoxinExotoxin
    LPS: Lipid A (toxic) and Polysaccharide on OUTER cell membrane
    Small
    Non-specific
    Low toxicity
    Fever and shock via TNF-alpha and IL1
    Gram -
    Poorly antigenic so always comes about!
    Secreted Protein (polypeptide)
    Large
    Specific - enzymes!
    High toxicity

    Non-pyrogenic
    Gram + and -
    Antigenic so vaccine is available
    Denatured by boiling


    Endotoxin

    LPS binds to TLR4 (toll like receptor) on macrophage → Proinflammatory cytokines released → Pyrexia, inflammation

    Causes:
    • Activate clotting: Activate Hageman factor → clotting, thus depleting platelet and clotting factors → Hemorrhage
      • DIC!!!
    • Activate innate
      • c3a, c5a
      • neutrophil, histamine release
      • suppurative
    • Low BP
      • Prekallikrein → Kallikrein turns kininogen to kinin (e.g. bradykinin)
      • Vasodilation and edema

    Exotoxin types
    1. superantigens (Type I toxins): bind to a receptor on the cell surface and stimulate intracellular signaling pathways
      1. Staphylococcus aureus and Streptococcus pyogenes: Bridge MHCII and TcR on most T cells
    2. exotoxins that damage host cell membranes (Type II toxins)
      1. alpha toxin (lecithinase): increases the permeability of capillaries and muscle cells by breaking down lecithin in cytoplasmic membranes. This results in the gross edema (def) of gas gangrene e.g. PLC from C. perfringens, which causes gas gangrene
      2. kappa toxin (collagenase): breaks down supportive connective tissue (collagen) resulting in the mushy lesions of gas gangrene.
      3. mu toxin (hyaluronidase): breaks down the tissue cement that holds cells together in tissue.
    3. A-B toxins and other toxin that interfere with host cell function
      1. The 'B'-subunit (binding) attaches to target regions on cell membranes → Endocytosis. The A-B toxin endosome becomes acidic as H+ comes in, causing A to dissociate and B to go back to membrane.
      2. 'A'-subunit (active) enters through the membrane and possesses enzymatic function that affects internal cellular bio-mechanism
    Examples of Exotoxin
    • Cholera toxin
      • AB subunit
        • A dissociates and ADP-ribosylation Gs to activate it → cAMP → cAMP activated CFTR → Cl- Efflux → Diarrhea
    • Clostridum perfrinogen: alpha-toxin Phospholipase C
    • Streptococci: Streptolysin → Brust RBC so bacteria can feed on its contents


    Prion - vCJD
    • Brain disease that is incurable and fatal
    • Human form of mad cow disease (bovine spongiform encephalopathy BSE is the cause of variant Creutzfeldt–Jakob disease in humans)
    • Long incubation period
    • Transmission: Eating contaminated beef, blood donation
    • Morphology: Brain holes and sponge-like
    • Prior diseases are caused by infectious protein which catalyzes conformation of change of a normal protein into an abnormal protein.
    • PrPc conformation in neurones
    • Contaminated Food → PrPSc protein induces PrPc to change to PrPSc → PrPSc out of cell and infect other neurones → accumulates over time and gets deposited as dense aggregates

    Virus - Measle, polio, HIV

    Rotavirus: Fecal oral source

    Enter enterocyte via VP4, replicates and secretes NSP4 (nonstructural protein: viral enterotoxin)

    NSP4 causes osmotic diarrhea
    • inhibits SGLT1-mediated Na+-D-glucose symport → osmotic pressure
    • open gaps in cell → H2o go out


    Virus invasion of the infected villi → Cell death → Villi atrophy → Malabsorption

    Poliomyelitis: Fecal-oral source
    Binds to CD155 of nerve → Cause cell death especially anterior horn
    1. Invasive stage, affects the nasopharynx, the tonsils - sore throat, chills. Cervial lymph nodes and Payer’s patches - constipation, diarrhea
    2. Pre-paralytic stage, from lymph nodes to bloodstream into CNS
    3. Paralytic stage, Bulbar polio affects the cranial nerves and is fatal. Spinal polio affects the anterior horn cell. Bulbo-spinal polio affects the cranial nerves and the anterior horn cell.

    Measles: Airborne
    • CD46 bind to in upper respiratory tract
    • Make fusion protein → Cells fuse (syncytia) → escape extracellular immune by living within the syncytia
    • Fatalities caused by autoimmune encephalomyelitis

    Bacteria - Pneumonia, Cholera


    Mannitol salt agar: Selective media (encourage growth of certain bacteria and inhibiting others)
    • High salt concentration: Good for Staphylococci
    • Gram + staphylococci fermenting mannitol: Media turns yellow
    • Gram + staphylococci not fermenting mannitol: Media does not change color (pink)
    • Gram + streptococci: inhibited growth
    • Gram - : inhibited growth


    Blood agar: Differential media
    β-hemolytic(yellow) - complete lysis of RBC by colony - Streptococcus haemolyticus
    α-hemolysis (green) - partial lyse - Streptococcus viridans
    γ-hemolysis: Non-hemolytic

    MacConkey agar
    Contain bile salt to inhibit gram +
    And to see if lactose fermenting

    Staph grow as grapes
    Strep grow as pairs

    Bacterial membranes

    inner membrane periplasmic space peptidoglycan outer membrane

    Transpeptidase aka pencillin-binding protein

    gram -: periplasmic space
    gram +: periplasm only

    nam + nag in cell membrane and then sent to periplasm
    nam + amino acid
    Nam x nam crosslinked via opposing aminoacids via transpeptidase (PBP) thus forming many layers!

    b-lactam: cephalosporin and penicillin

    • beta lactam ring - binds to transpeptidase → complex
    • high internal osmotic pressure burst
    • stimulates autolysin release -> digest existing cell wall - bacteriosidal agents!

    bacterial resistance
    1. endocytosis uptake of naked dna containing resistance gene →  homologous transformation (from naked to host dna) → altered PBP - reduced affinity for b-lactam
    2. resistance plasmid via conjugation (come to close contact and small channel between to allow plasmid to go across and transcribed --> make beta-lactamase!) - inactivates drug before it enters cell

    Bacterial conjugation



    conjug - transfer of DNA that require direct transfer between recipient and donor

    F+ cells have f plasmid - can make F pillus - the donor
    recipient cells do not have F plasmid - F-

    F pilli of donor cell x receptor on recipient - fuse
    endonuclease cleaves one strand of the plasmid at the origin of transfer --> a single strand beginning at origin of transfer of F plasmid enters F- cells (the T-TNA to be transferred). meanwhile a complementary strand to the single stranded plasmid remaining in the donor is synthesized via rolling circle mechanism

    once the plasmid is in the recipient, a complementary strand is made -> F- becomes F+!

    F plasmid = F factor (ferility factor)


    gram +: release b-lactamase from cell to extracellular environment

    gram -: b-lactamase retains in periplasm

    bacterial  circular double stranded dna
    divides via binary fission
    1. make identical copy of circular dna (helicase to break hydrogen bonds, opening replication fork where it begins by dna polymerase to make complementary strand , move forward --- supercoiling - removed by dna gyrase (topoisomerase 2), - interlinked daughter dna molecule

    to make it come apart, topoisomerase 4 separate!!!!

    semiconservative replication

    Overview of bacterial transcription and translocation
    1. bacterial dna + rna polymerase makes mrna transcript
    2. mrna to 50s (large) x30s (small) ribosomal subunit to translate (align trna - each trna carrying amino acid form polypeptide chain translation) until reach stop signal to release polypeptide chain

     



    Eukaryotes have 80S ribosomes, each consisting of a small (40S) and large (60S) subunit.

    Prokaryotes have 70S ribosomes, each consisting of a small (30S) and a large (50S)

    Buy AT 30, CELL at 50
    Drugs acting on 30s ribosome subunits :

    • Aminoglycosides ( Including Streptomycin, Gentamicin, Amikacin, Tobramycin)
    • Tetracyclines

    Drugs acting on 50s ribosome subunits :
    • Chloramphenicol
    • Erythromycin
    • Lincomycin
    • cLindamycin


    E. Coli

    Gram-negative rod-shaped bacterium that is commonly found in the lower intestine of warm-blooded organisms (endotherms).Most E. coli strains are harmless, but some, such as serotype O157:H7, can cause serious food poisoning in humans, and are occasionally responsible for product recalls.[1][2] The harmless strains are part of the normal flora of the gut, and can benefit their hosts by producing vitamin K2,[3] and by preventing the establishment of pathogenic bacteria within the intestine.[4][5]

    fecal contamination



    Food poisoning caused by E. coli is usually caused by eating unwashed vegetables or undercooked meat.

    E. coli can harbour both heat-stable ST and heat-labile LT enterotoxins. The latter, termed LT, contains one A subunit and five B subunits arranged into one holotoxin, and is highly similar in structure and function to cholera toxins. The B subunits assist in adherence and entry of the toxin into host intestinal cells, while the A subunit is cleaved and prevents cells from absorbing water, causing diarrhea. LT is secreted by the Type 2 secretion pathway.[28] If E. coli bacteria escape the intestinal tract through a perforation (for example from an ulcer, a ruptured appendix, or due to a surgical error) and enter the abdomen, they usually cause peritonitis that can be fatal without prompt treatment. However, E. coli are extremely sensitive to such antibiotics as streptomycin or gentamicin.

    fimbrial adhesins (projections from the bacterial cell surface) to bind enterocyte cells in the small intestine.

    Hemolytic-Uremic Syndrome


    Damage to endothelial cells is the primary event in the pathogenesis of hemolytic-uremic syndrome (HUS). The cardinal lesion is composed of arteriolar and capillary microthrombi (thrombotic microangiopathy [TMA]) and red blood cell (RBC) fragmentation.
    red blood cells are destroyed and the kidneys fail


    E. coli O157:H7 is believed to cause more than 80 percent of the STEC infections that lead to hemolytic uremic syndrome.12 This microorganism is not a normal part of the human intestinal flora13 but is present in the intestines of 1 percent of healthy beef cattle; the meat can become contaminated during the slaughter and processing of the anima


    .E. coli bacteria also may be transmitted by contact with persons who inadequately wash their hands, resulting in fecal and oral contamination and transmission.14

    The classic triad of features for hemolytic uremic syndrome consists of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure

    Hematologic findings include destruction and fragmentation of erythrocytes that result in microangiopathic hemolytic anemia.

    Ninety-two percent of patients with hemolytic uremic syndrome develop thrombocytopenia, which results from entrapment of platelets in the organs


    Acute renal failure results when micro-thrombi are deposited in kidney parenchyma. This manifests in the form of hypertension associated with oliguria and anuria, which are early signs of acute renal failure.
    1. Cholera toxin released from Vibrio cholerae → Binds to enterocytes using its pentameric B subunit of the toxin with the GM1 ganglioside receptor on the intestinal cell, triggering endocytosis of the toxin.  
    2. Enzymatic A1 fragment of toxin A subunit activates Gs → more cAMP
    3. More cAMP activate CFTR → Continual Cl- efflux in intestine