Test 2-1 Flashcards
five types of host directed defenses
extracellular/intracellurar bacteria
fungi
viruses
parasites
Leprosy example:
tuberculo - minimal skin damage - control bacteria via cell-mediated
lepromatous leprosy - crazy skin damage - made humoral not cell mediated
bacteria so need cell mediated immunity not humoral so lepromatous is much worse
features of anti-microbial immunity
- microbes ahve strategies to evade immune response - if they evade and effectively invade a host then = disease
- strong immune response often causes host tissue damage
extracellular bacteria
- infect us but dont need to get into cells
- tissue destruction –> induces inflammation + toxin release
host resp to extracellular bac
kill bacteria and neutralize toxin
1st line of defense against extracellular bacteria
phagocytosis
extracellular bacteria alternate complement path
bac cell wall compenents can activate complement to lyse or opsonize bacteria
humoral immunity and extracellular bac
main protective response:
- IgG opsonises
- IgG toxin-specific antibodies to neutralize
- IgM and IgG activate classical complement to lyse
bacterial evasion of apoptosis
- polysaccharide capsule to evade phagocytosis
- inhibit alternate path completment activation
deleterious effect of the immune response to extracellular bac
- septic shock: many gram neg and some gram positive bac can induce macrophages to realse TNG and IL-1
- superantigens: bacerial and viral extraellular- bind t-cell and this causes the immune cells to dump TNF = toxic septic shock! Dying because making TNF-alpha
- rheumatic fever - cross reactive antibodies made for bactiera that also have affinity for sarcolemma proteins in heart = caditis
- pststreptococcal glomerulonephritis - infection with streptococci. antibidies that form immune complexes with bacterial antigens get lodged in kindey = nephritis
general principles of intracellular bacteria
- survivee and mult in macrophages
- inaccessible to circulating antibodies
- strtegies that allow them to thrive in phagocytic cells
innate immunity and intracellular bactera..
- innate is inneffective… some bacteria not killed when ingested— they want to be ingested
- NK cell activated by IL-12 from macrophages ==>NK produces interferon-gamma = effects macrophage to be EVEN MORE activated and can kill the intracellular bacteria
- some intracellular klled but need addaptive for full erradication
delayed type hyperactivity (DHT-like)
type IV adaptive immune reaction to intracellular bactrei
adaptive immune response and intracellular bacteria
- DHT like (delayed type hyperactivity-type IV) -
- t-cells become activated –> release interferon-gamma —> activated macrophages MAY eliminate the bacteria
- if cant kill it - macrophages surround the icrobes = granulomas - prevents spread (like an abcess for innate but this is adaptive
granuloma
adaptive immune response way to prevent spread of intracellular bacteria
abcess
innate immune response (fromed by neutrophils?) to wall off agitating agent
evasion of imunity - intracellular bacteria
- mycobacterium - inh fusion of phagosomes and lysosomes. May also scavenge reactive oxygen intermediates to prevent bacterial killing
- listeria monocytogenes - distrupts phagosome –> escapes into cytosol (show up on class I mHC)
- CTLs generated if the bacteria escape fom phagosomes into cytosol or if bacterial antigens transported into cytosol
deleterious effec tof immune - intracellular bac
-granulomas may compromise tissue function so although the mycobacteria that end up getting showed into the granulomas do not cause tissue damage the granulomas that are made DO CAUSE TISSUE DAMAGE AND IMPAIRMENT OF FUNCTION
viruses - what are they what do they do
can lyse host cells (called cytopathic effect)
cytopathic effect
viruses that lyse host cells
main form of innate immunity against viruses
TYPE 1 - IFN-alpha and beta
==>produced and paracrine inhibit viral replication in surrounding host cells
-increase in class i MHC
first line of defense against virus infected cells=
NK cells - they know that the cell is virus infected bc the virus downregulates MHC class I receptors on surface
- if they dont downregulate MHC class I then CTL kill them
- NK cell have receptors then need to check up on the presence of MHC class I receptors
adaptive immunity and viruses
-humoral is important early IF antibodies are present (ex VACCINE or previous infection or mother to fetus) = prevent virus from binding to target host; opsonize virus; activate complement to lyse viral envelopes
CTLs and adaptive immunity for viruses
principal compnent during established virus infection - so virus has made some of its proteins - these proteins end up on class I MHC
evasion of immunity -viruses
- viruses can alter their antigens:
- —> HIVhas error prone reverse transcriptase= point mutation= antigenic variability
- —> influenza reassortants produce antigenic alteration - different strains that share genes
- some viruses prevent class I MHC expression of viral peptides = these cells avoid CTLs
- HIV infects/kills CD4 Tcells = prevent immune response
deleterious effects of immune resp viruses
- CTLs may mediate pathologic lesions in some viral disease states: Hep B infection induces CTL response that destroys the liver (immunodef indiv dont get liver damage)
- some viruses express proteins with homology for host cell proteins: immune response against virus but cross reacting with host tissue == molecular mimicry
molecular mimicry
deleterious effec tof immune system with viruese - viral antigens look like (mimc) host proteins so the antibodies also destroy host proteins/cells (cross reactivity)
fungal diseases general principles
- important cause of morbidity and mortality
- inc number of opportunistic fungal infections
- immunity needs humoral and cell-mediated elements
- immunocompromised patients at risk
innate immunity and fungi
- neutrophils are main mediators
- phagocytosis–> lysosomal enzymes and reactive oxygen intermediates
- low neutrophil count (neutropenic?) highly sucsceptible to fungal inf
adaptive immunity and fungi
- Th1 mediated is the most important (CTLs involved)
- granuloma formation
- antibodies??? need more research
general principles parasites
- infectious disease brought about by protozoa and helminths
- complex life cycle
innate immunity - parasites
innate immunity - not really effective.
-macrophages can eat (protozoa) it but many are resistant
-helminths outer layer can activate alternative complement path but are resistant to effects of complement
thick teguments = resistance to neutrophils and macrophaes
adaptive immunite - parasite
- protozoa that macrophage eats and cant destroy are activated by CDt-cells that secrete interferon-gamma to activate teh macrophage
- Th1 mediated immunty against eggs in liver = CD4 t-cells will recruit macrophages to wall off the eggs
- IgE + eosinophils during ADCC (Th2 immunity) may be used against worms
evasion of immunity - parasite
- hide in intestinal lumen or protective cysts
- coat with host proteins
- outer surface that inh complement
- extracellular enzymes –> cleave membrane bound antibody
- vary surface antigen
- shed antigens spontaneously after bound by antibody
deleterrious effects - parasites
- chronic parasite infestations = immune complexes lodged in bv and kidney = vasculitis and nephritis
- egs in liver = liver fibrosis (granulomas)=disruption of venous flow to liver = portal hypertension and cirrhosis
- flaria worms= lodge in lymphatic channels = sever fibrosis and restriction of lymph flow = sever lymphedema
4 types of hypersensitivities and definition
host responses to angiten that develop into deleterious effects, including tissue damage and even death - (OVERLY ACTIVE IMMUNE RESPONSE)
I - allergy and anaphylaxis
II - antibody-mediated cytotoxicity
III - Immune complex disease
IV - delayed type hypersensitivity
Types I, II, and III involve…
antivbody - IgG
Type IV involves
cell mediated immunity
allergy and anaphylaxis Type I definition
rapidly progressing immune reaction through antigen binding to surface of IgE coated basophils or mast cells
dif between allergies and anaphylaxis
same mechanism but allergy is LOCALIZED
anaphylaxis is WHOLE BODY and the response is systemic - people die
anaphylaxis induced by and how
- allergens: venoms, penicillin, nuts….
- direct into bloodstream or rapidly absorbed by gut —> systemic mast cell activation == potential anaphylaxis
ONLY TAKES A VERY SMALL AMT
what is atopy
- people who are more susceptible to type I hypersensitivity (tend to develop allergies) - may be genetic or enviromental
- these people tend to make IgE for allergens - IgE normally responds to parasites
- responses in skin, airways, & gut
- Th2 responses = absence of inflammation (which allergens dont exist) involves antibody = durp Th2
genetics and environment to atopy
- early exposure combined with susceptible genetics = high probability of atopy
- we are growing up in too clean an environment hypothesis - we arent being exposed to the pathogens normally would be bc its so clean - less expouse = less Th1 = less Th1 means that less suppression
- frequency increasing in more developed countries
allergens that promote atropy and Th2/IgE
- low dose
- low molecular weight
- highly soluble
basophil location vs mast cell location
bloodstream //// in tissues
development of anaphylaxis
1) exposure to allergen —> IgE (NO ANAPHYLAXIS ON 1ST EXPOSURE)
- IgE production begins with first exposure
- IgE binds Fc receptors (FCERI) on basophils + mast cells (most IgE in serum is bound to basopils or mast cells)
2) (MEMORY RESPONSE)-subsequent exporuse to allergen binds surface bound IgE and crosslinking –> cells release granules contents (HISTAMINE)
3) granule contents = vasoactive compounds = edema and smooth muscle contraction – symptoms or death (2-30 min after secondary exposure)
penicillin is a …
hapten - so it must couple to elf proteins to stimulate IgE response
people who “dont have any allergies”
still make IgE but not as much and the mast cells/basophils arent as coated
eosinophils and atopia
higher levels in atopic people - normally attach parasites but…
Late phase response (type I)
- occurs 6-8 hrs after exposure through secretion of prostaglanidns, leukotrienes, chemokines, and cytokines by mast cells
- 2nd phase of smooth muscle contraction
- sustained edema
- recruitment of eosinophils and Th2 cells
- remodeling of tissue - ex) smooth muscle hypertrophy and hyperplasia
- may lead to chronic asthma and associataed airway hyperreactivity
mast cell granule contents and effects
- -histamine - bronchial smooth muscle contraton & inc vascular permeability (LUNGS MAJOR ORGAN AFEFCTED)* Lungs fill up with fluid edema and airways close up
- proteases - activate matrix matalloproteinases –> cleave tissue matrix proteins to acuse damage
- TnF-alpha - promotes inflammation
- eosinophil chemotactic factor of anaphylaxis - accumulation of eosinophils locally or in blood steram –> attempt to counteract effects of histamine
leukotrienes (LT)
LCD, LTD, and LTE=
- most potent substances known that cause smooth muscle contraction and inc vascular permeability (SAME EFFECT AS HISTAMINE)
- released more slowly (synthesized)+longer effect
contast leuko and histamine…
histamine is released quickly in granules = shorter effect
leuko released slowly = longer effect
treatment for Type I
- -epinephrine: binds to B-adrenergic receptor = increase cAMP = relaxes bronchial smooth muscles, tightens endothelial cell junctions, stimulates heart - ONLY ONE THAT REVERSES ANAPHYLAXES*
- antihistamines - block binding of histamine to its receptor
- cromolyn sodium & theophyline - block degrenulation
- allergy shots: repeated s.c. allergen ingections =IgG blocking antibody
Only treatment that reverses anaphylaxis?
epinephrine
type II hypersensitivity is and types
damage mediated by antibody - (antibody mediated cytotoxicity)
- complement-mediated reactions
- antibody dependent cell-mediated cytotoxicity (ADCC)
- hemolytic disease of the newborn
- non-cytotoxic reaction with cell receptors
complement mediated reaction mechanisms:
Type II hypersensitivity
- IgG and IgM activate classical complement cascade = cells lyse
- opsonization with C3b = ingestion of RBC by phagocytes
- trasfusion reactions, autoimmune hemolytic anemia, drug reactions
ADCC mechanism
type II hypersensitivity
-tumor cells or virus infected cells bound by IgG lysed by NK cells ,moncytes, or neutrophils
-can be directed at normal tissue if autoantibodies are present
(stuff is too big to phagocytose sometimes)
hemolytic disease of the newborn principles:
Type II
- RH- mother makes IgG to Rh antigen expressed by kids RH+ RBCs
- first Rh+ child stimulates immune response but is unaffected
- subsequent Rh+ fetus has trouble… mothers IgG response destroys RBC by macrophages in the spleen and liver
to prevent: Rh- mother needs anti-Rh antibodies == binds to fetal cells in mother == removal == prevent sensitization (moms immune system never sees Rh+ baby RBC
non-cytotoxic reactions:
no destruction of cells
-graves diease: antibodies to TSH receptor causes overproduction of thyroid hromones b/c no feedback to turn off–> hyperthyroidism
-myasthenia gravis: antibodies to acetylcholine receptor bocks nerve impulse transmission to muscles
(AUTOIMMUNE EX^)
type III
immune complex disease: a lot of antibodies made and against a lot of antigen and they complex together to make complex = lodges in kidney or whatever
- induced by -
1) autoimmuine -Lupus (SLE) or rheumatoid arthritis
2) infectious disease -subacute bacterial endocarditis, chronic viral hepatitis, or poststreptococcal glomerulonephritis
3) inhaled allergens - farmers lung (mold spores or hay dust)
pathogens Type III
- antigen +antibody = immune complex
- optimal proportions of antibody and antigen are required
- immune complex size important –> medium sized immune complexes cause problems
- OPTIMAL AMOUNTS OF BOTH IS KEY! (too small complexes can be peed out and too large complexes can be handled by phagocytes – MEDIUM SIZES ARE THE PROBLEM
pathogen type III process:
1) optimal antibody and antigen concentrations reached and complexes made
2) complexes activate complement== production of C5a ===> neutrophil accumulation and degranulation
3) degranulation contains: lysosomal enzymes damage tissue= fever, urticaria, arthritis, lymph node enlargement , proteinuria
SKIN AND KIDNEYS MOST AFFECTED
GET STUCK = ACTIVATE COMPLEMENT = NEUTROPHILS = NEUTROPHIL DAMAGE
pathogen process affects which organs mostly:
skin and kidneys
tpye III
serum sickness
foreign serum to neutralize some poinson
foreign serums containa whole bunch of other proteins which your immune system can produce an immune or hypersensitive response to
-used to help allograft transplantations
purpose of immune complex removal
if remove immune complexes from normal immune responses can avoid immune complex disease
immune complex removal steps:
1) RBC with CR1 proteins bind C3b or C4b on immune complex
2) shuttled to liver or spleen
3) immune complexes remvoed from RBC by macrophages
immune complex response in overwhelmed in which hypersensitivity?
Type III
type IV hypersensitivity is:
CELL MEDIATED IMMUNITY!
type IV hypersensitivity principles;
- manifests 24-72 hrs after exposure to antigen
- tuberculin reaction, contact dermatitis, delayed graft rejection
- memory response: requires prior sensitization to antigen
EX)TB SKIN TEST takes a few days to read
contact dermatitis:
type IV
- skin exposure to nickel, chromium, cosmetics, hair dye, poison oak, and poison ivy… etc
- small molecules complexed with skin proteins are presented by antigen-persenting cells to t-helper cells
- pentadecacatechol (poison ivy leaf oil) is lipid soluble – crosses cell membrane to modify intracellular proteins –> expressed on class I MHC for recognition by CTLs -
tuberculin skin reaction:
PART 1)
-PPD injected intradermally –> vascular endohelium and/or macrophages present antigen to memory T-cells
-endothelial cells upreg expression of VCAM-1 to bind memory T-helper cell-expressed VLA-4
-T-cells migrate into skin
-small portion of migrating memory t cells will be be specific for PPD
PART 2)
-antigen specific t-cells interact with antigen-expressing macropages
-memory t-cells activate and secrete interferon-gamma
-interferon gamme increases macrophage class II MHC ==> better antigen presentation
-more t-cells activated –> more interferon -gamma ==> amplified rxn
PART 3)
-large # macrophages activated
-tissue damage occurs
-redness and induration characteristic of positive PPD skin test
-PPD neg=antigen done too small to stimulate primary immune response
-memory responses require smaller doses of antigen
granuloma formation
- antigen not removed = DTH = granuloma (wall of bacteria)
- same basic DTH mech but different outcome
- macrophages ingest organism, surrounded by other macrophages
- CD4 lymphs surround macrophages to maintain macrophage activation and structural integrity of granuloma
structural integrity of granuloma upkey by
CD4 lymphocytes that surround macrophages
granuloma stuff
- can compromise normal lung function
- AIDS patients = loss of CD4 cells =inability to maintain a previous granuloma = escape of bacteria = systemic infection
- AIDS patients that get infected with TB dont develop granulomas
autologous graft
a graft transplanted from an individual to the same individual. An example includes bone marrow or blood harvested and saved for a future period of time
Syngeneic graft
is a transplant between two genetically identical individuals (i.e. identical twins).
allogeneic graft
is a transplant between two genetically dissimilar individuals of the same species. Alloantigens are those antigens which are recognized by the graft recipient as being foreign. This type is the most common form of transplant.
xenogeneic graft
is a transplant between members of two different species. Xenoantigens are those antigens which are recognized by the graft recipient as being foreign. Recent examples include baboon hearts and baboon livers. Xenografts, from pigs or primates, are being intensively studied for transplantation given the scarcity of human organs available to those who need them. Pig organs are similar in size to that of humans and pigs are easily farmed.
orthotopic transplant
a graft placed in its normal anatomical location
heterotropic transplant
placed in an anatomically different site (ex heart bypass)
immunologically priviledged sites
no risk of rejection: brain eye testis uterus hamster cheek pouch
mechanisms of privilege
- extracellular fluid that bathes these tissues doesnt leave trhrough the conventional lymph system
- TGF-beta, inh cytokine, produced at these sites
- Fas ligand - reacts with Ras on lymphocytes to induce apoptosis
Sympathetic ophthalmia
one eye is damaged by trauma and automimune response to eye proteins threatents undamaged eye
transplantation laws
1) b/w identical twins are never rejected
2) bw genetically dissimilar individuals are almost always rejected without immunosuppression
3) grafts derived from children will be rejected by either parent. children would express that either parent sees as foreign
So many polymorphs of class I and II MHC
hyperacute rejection
- takes place within minutes of attaching the graft to recipeitns blood supply
- mediated by pre-existing antibodies ex)ABO blood groups
- difficult to treat
- uncommon
acute rejection
- takes place within 1 month of transplantation
- treated with inc immunosuppression ex)high dose steroid therapy or antit-cell antibodies
- two types:
- —>acute humoral rejection: Antibody and complement-mediated lysis of graft tissue=necrosis of the blood vessel walls
- —-> acute cellular rejection: Cell-mediated lysis of graft tissue by CTLs, NK cells, and/or macrophages
chronic rejection
- occurs after months or years of transplant
- mechanism unknown: may involve-mediated injury to the graft vasculature or delayed-type hypersensitivity (DHT) reactions
- fibrosis and deposition of collagen are characteristic with accelerated arteriosclerosis resulting in vascular occlusion
- unresponsive to inc immunosuppresiion
alloreactivity
- t cells need antigen and self MHC proteins –allografts express foreing MHC proteins..???
- recipient APCs could present foreign MHC peptides in conjunction with self class II MHC to activate t-helper cells: does occur but cannot be the primary mechanism for t-helper cell activation, since CTls could not lyse the foreign MHC class I bearing cell grafts
- alloreactivity is t-cell receptors that see self MHC and foreign peptide can also see foreign MHC and self peptide to become activated
- foreign MHC protein MIMICS CONFORMATION OF BOTH SELF MHC AND FOREIGN PEPTIDE - the SELF T-cell receptor THINKS that its seeing what it should be seeing when it binds foergin MHC and self antigen.
alloreactivity events:
1) “passenger leukocytes (donor APC) stimulate CD4 alloreactive t-cells to become activated
2) alloreactive CD4 t-helper cells provide IL2 and IFN-gamma to alloreactive CD8 t-cells to produce CTLs that can lyse graft cells or alloreactive b-cells to produce anti-graft antibodies
effector mechanisms in allograft rejection
- alloreactive CTLs can directly lyse graft cells
- alloreactive CD4 t-heler activate macrophages = destruction of graft tissue through DTH response
- alloantibodies activate complement to destroy graft blood vessels
preventing rejection strategies
1) try to mathc donor recipient as best as possible. determine class I and II MHC protein expression via serological/molecular techniques
2) immunosuppression - a) corticosteroid therapy = lyse immature thymocytes and block release ofcytokines from macrophages; infections and malignancies can develop b) cyclosporine=drug of choice for immunosuppression –> (inh calcineurin) inh IL2 and IFN-gamma gene expression, preventing activation of cell mediated immunity (not as effective as inh secondary immune responses compared to primary AND NEPHROTOXIC c) anti-lymphocyte globulin = horse serum–> kills wanted and unwanted (t-cells) lymphocytes but can reverse acute graft rejection (serum sickness side effect)
3) deplete the passenger leukocytes - purge the kidney cell of the APC cells before transplantation
bone marrow transplantation
- cancer and or immunodef peope undergo radiation to kill bone marrow and donor bone marrow is administered with “homing” to bone marrow
- different than all other forms since immune bone marrow has the precursors to all immune cells SO instead of your bone marrow trying to get rid of the transplanted organ it is trying to get rid of ALL OF YOU since you are completely foreign to the new bone marrow (graft vs host disease)
graft vs hsot disease
differentiates bone marrow transp from all other types:
1) acute GVHD: quickly following bone marrow transplantation - involves epithelial cell necrosis of the skin, liver, and GI tract. potentially fatal
2) chronic GVHD: fobrosis in organs causing dysfunction. Fatal if severly affects critical organs. potentailly fatal
reduce risk of GVHD…
- antiCD3 monoclonal antibodies (with complement) decrease incidence of GVHD but reduces chances of engragtment
- getting rid of t-cells that attach body in GVHD
graft vs leukemia effect:
helps prevent recurrence of cancer bc the GVHD reaction removes minimal residual disease. Fine line bw allowing GVHD and risking cancer recurrence and much GVHD = pot life threatening
-a little bit of GVHD is ok and helpful
bone marrow donation:
- siblings provide the best opportunity for an HLA match
- relatively safe
- if no family screen donor registry for close match
- needle orf leukapheresis for peripheral stem cells (give G-CSF to mobilize donor bone marrow stem cells into blood and sort cells by flow cytometry -reduces risk of minimal residual disease and is less invasive)
skin grafts -
- used primarily in the treatment of burn victims. -Autologous grafts are typically the most successful and involve harvesting skin from other body sites.
- Allogeneic grafts using frozen deposits from a tissue bank can be used for a short period with immunosuppression in the event that autologous tissue isn’t available, but the graft is usually rejected when immunosuppressive therapy is stopped.
kidney transplants:
performed annually - cadaveric donors provide most kidneys but living unrelated donors are increasing
liver transplants
transplanted even in the face of pre-existing antibodies. Carries large numbers of donor lymphocytes which inc risk of GVHD. Liver can regenerate so inc in living related donors
heart transplant
high success rates
antibody mediated vascular injury –> high incidence of new atherosclerotic disease in coronary arteries
pancreas
- transplantation performed to treat diabetes mellitus
- newer approach is to transplant insulin producing islet cells along
- limited success
fetal immunology… fetus is a
fetus is a naturally concurring allograft
fetal immuno mechanisms
- trophoblast cells dont express paternal MHC proteins. in addition HLA-G, an MHC class I like protein keeps NK cells from becmoing activated by the trophoblast cells that experss no MHC proteins
- trophoblast cells may secrete inh cytokines such as YGF-beta
- tryptophan is broken down at the fetal maternal interface by the enzyme indolamine 2,3 dioxygenase. tryptophan-starved t lymphocytes react poorly to antigen
autoimmunity general principles
- all normal healthy indiv have mature self reactive lymphocytes
- Need to breach both the perihperal and central tollerance mechanisms: - central-bone marrow autoreactive lymphocytes not deleted in BM and thymus - peripheral-normal inh mech fail in periphery
multiple system autoimmune diseases are common n the same indiv or family bc
-once you lose that lymphocyte regulation it can become reactive against anything –> may be genetic predisposition
predisposing factors to autoimmunity
- abnormalities of lymphocytes and APCs
- genetic predisposition
- microbial infections
- tissue injury (autoreactive CTLs; circulating autoantibodies; immune complexes)
vertical transmission of antibodies
maternal autoimmune IgG may affect developingfetus/neonate:
- effects disappear after brth when the antibodies are catabolized
- some organ damage may be irreversible (ex: Heart damage by antibodies = bradycardia
sequestered antigens theory of dev of autoimmunity
- damage or trauma to some prtoeins thatthe body has ever seem before and it start the autoimmune issue
- released into the circulatio through trauma or infection
- not availabe to induce tolerance
- ex) myein basic protein (Blood brain barrier), sperm antigens, heart muscle antigens, eye lens proteins, sympathetic ophthalmia
microbe theory of dev for autoimmunity
- microbial protein homology with human protein
- microbial mimicry may resemble self antigens closely enough to break tolerance
- mycoplasma infections = antibodies can cross react with an antigen on RBC to cause destruction
- cross reaction of streptococcal autoantibodies with heart valve tissue = rheumatic fever
MHC for ankylosing spondylitis is
HLA B27 (class I MHC)
MHC for type I diabete is
DR3/DR4 heterozygote (class II MHC)
innapropriate expression of MHC proteins theory of autoimmune development
- cells that dont normally express MHC molecules may do so and this activates T-cels (especially class II)
- expression of MHC proteins with self pepides durig t-cell selection in thymus might allow positive selection of autoreactive t-cells, but might not bind with high enough affinity to elicit negative selection
- other genes that occur near a given HLA allele (and inherited together) might be responsible
- vast majority of individuals with a HLA allele will not dev disease++ other factors involced
autoimmune hemolytic anemia (organ specific)
RBC antibodies produced against RBC membrane proteins
- causes lysis and anemia
- opsonization –> removal by phagocytic cells in spleen
- intravascular hemolysis - complement activated
- extravascular hemolysis - antibodies opsonize RBC so RBC can be takeen out in spleen or liver
good pasture syndrome: (organ specific)
- autoantibodies to the alpha3 chain of type IV collagen (basement membrane collagen) of the lung (alveoli) and kidney (glomeruli) (NOT TYPE IV HYPERSENSITIVITY)
- causes complement activation == ckindey damage, pulmonary hemorrhage, death within a few motnhs
- smooth ribon like appearance
Pernicious anemia (organ specific)
- autoantibodies to intrinsic factor and/or gastric parietal cells
- decrease absorption of vit B12 = abnormal erythropoiesis/anemia
hashimotos thyroiditis (organ specific)
- hypothyroid state
- autoantibodies and autoreactive t-cells to thyroid gland proteins
flurescent kidney biopsy with smooth ribbon like appearance
board question= good pasture syndrom
Idiopathic thrombocytopenia purpura (ITP) (organ specific)
- platelets destroyed by autoantibodies to platelet membrane proteins
- purpura=purple skin lesions due to epidermal hemorrhage
- IVKG can prevent destruction of platelets
vtiligo (organ specific)
depigmentation of skin due to destruction of melanocytes
graves disease (organ specific)
autoantibodies against TSH receptor
-hyperthyroidism
myasthenia gravis (organ specific)
autoantibodies to alpha chain of nicotinic acetylcholine receptor on skeletal muscle cells at neuromuscular junctions
-blockage of neuromuscular transmssion = muscle weakness and paralysis
type I diabetes: (organ specific)
insulin dependent diabetes mellitus - glucose intolerance and hyperglycemia through immune mediated destruction of insulin secreting beta cells in the pancreas
- type 1A = autoantibodies to beta cells. despite diagnostic worth of antibodies, autoreactive t-cells mediate destruction of beta cells
- damage to beta cells results in dec insulin and inc blood glucose
multiple sclerosis: (organ specific)
autoimmune demyelinating disease of CNS
- 1 to 2 decades to produce neurologic disability
- leading cause of nontraumatic neurological disability in your adults (avg age onset = 29years)
- relapsing-remitting and progressive forms of the disease –>progressive form = most serious disability
- therpies: interferon beta1b (s.c. on alternate das), inferon beta 1a (weejkly I>M> injections and I.v. steroids
- myelin specific CTLs cause demyelination by release of perforin
- myelin specific IgG binds to myelin surface to activate complement
- macrophages attracted to sites of inflammation and are induced to secrete nitric oxide = destroys nerve fibers
systemic lupus erythematosus (systemic autoimmune disease)
- multisystem disease mediated by a constellation of autoantibodies
- broad loss of regulatory control that sustains self-tolerance
- autoantibodies against numerous antigens including DNA, RNA, proteins, and ribonucleoproteins
- mos torgan systems can be affected - esp skin, joints, kidney
- 1:700 for females - more females affected
- butterly rash
- most tissue injury via immune complexes (type III hypersensitivity) (stuck in kidney); also RBC and WBC destruction directly by complement mediated lysis (type II hypersensitivity)
systemic lupus is what kind of hyperensitivity?
type II and type III
predisposition to lupus
1) genetic factors - if family member has inc incidence
2) nongenetic factors = drugs and sme viruses
- drug induced lupus = slow drug metaoblization = drugs can complex with nuleoproteins to generate autoimmunity -reverses upon removal of drug
3) immunologic factor: B cell hyperactivity, inc t-helper activity and or dec t-suppressor activity
rheumatoid arthritis (systemic autoimmune disease)
progressive inflammatory disease of joints = destruction of joint cartialage and inflammation of synovium
- more common in women
- pulmonary issues,cardiac,ocular manifestation as well
rhuematoid arthritic MHC is
HLA-DR4 haplotype
pathogenesis of rheumatoid arthritis
- inflammation of the synovium by some etiologic agent
- humoral and cell mediated immunty = immune complexes and DTH
- rheumatoid factor = IgM/IgG to Fc porton of IgG=immune complexes (antibody to another antibody)
what type of hypersensitivit yis rheumatoid arthritic?
type IV hypersensitivity
TNF-alpha and rheumatoid arthritic
- biologic agents control symptoms
- etanercept=TNF-alpha type II receptor fused to IgG1 antibody —> REMOVE TNF-ALPHA
- infliximab - chimeric mouse/human anti-TNF-alpha monoclonal antibody
sjogrens syndrome (systemic autoimmune disease)
- dry eyes and dry mouth bc of destruction lacrimal and salivary glands
- b and t cell influx into glands but not known whether CMI or humoral immunity responsible for damage
- occurs along or in conjuction with RA or SLE
- women mostly affected
- increases risk of lympoid malignancies
scleroderma (systemic autoimmune disease)
- hypersensitivy of collagen
- t-cells react to collagen – and body produces more collagen in cycle (IL1 and TNF-alpha produced)
- skin GI tract, heart muscles and lungs
polymyositis dermatomyositis
- polymyositis - muscle injury possibly brought about by CD4 and CD8 t-cells infiltrating muscles
- dermatomyositis - skin rash that often accompanies the polymyositis
- 25% have autoantibodies to histidyl tRNA synthetase (dianostic)
- coxsackie B virus could play role as it has been isolated in some patients
current therapies for autoimmune
1) no good cures only therapies
2) nonspecific immunosuppression with drugs decrease tissue injury
- coricosteroid use (prednisone)- antiinflam effects. side effects=bone mineral loss, weightgains, diabetes, fluid retention, skin thinning
- azathioprine and cyclophosphamide: cytotoxic drugs that interfere with DNA synthesis = eliminate dividing lymphocytes. side effects= bone marro suppression and damage to intestinal epith
- cyclosporine and tacrolimus - block activity of calcineurin = blocks transcription of IL 2. Nephrotoxic drugs
3) plasmapheresis- removes Ag-Ab complexes - short term alleviation of symptoms
