Core Immunology Flashcards
What is an allergy?
Undesirable, damaging, discomfort-producing and sometimes fatal reactions produced by the normal immune system directed against innocuous antigens in a pre-sensitized (immune) host.
What is type 1 hypersensitivity?
IgE exogenous 15-30 minutes wheal & flare basophils & eosinophil antibody pollen-hay fever allergic asthma
What is type 2 hypersensitivity?
IgG/IgM Ab response against combined self/foreign antigen at the cell surface- complement activation/phagocytosis/ADCC
Clinical features
Onset minutes to hours
Cell lysis and necrosis
Common antigens: Penicillin
Associated diseases
Erythroblastosis fetalis,
Goodpasture’s nephritis
What is type 3 hypersensitivity?
IgG/IgM Ab against soluble antigen- immune complex deposition
Clinical features
Onset 3-8h
Vasculitis
Traditional cause-serum sickness
Associated diseases: SLE , arthritis, nephritis etc
What is type 4 hypersensitivity?
Antigen specific T-cell mediated cytotoxicity
Clinical features
Delayed onset 48-72h
Erythema induration
Common antigen
Metals-e.g nickel
(tuberculin reaction)
Associated diseases Contact dermatitis
Why do we get allergies?
Those components of the immune system implicated in allergic responses are primarily involved in responses to parasitic infection
The immune system has evolved to generate a rapid tissue-based response to re-infection
The lack of infectious drive is a contributory factor in allergic disease
What are the Immune responses to parasitic disease?
- Increased levels of IgE
Total
Specific to pathogen – cross-reactive
-Tissue inflammation with:
Eosinophilia & Mastocytosis
Basophil infiltration
-Presence of CD4+ T cells secreting:
IL4, IL5 & IL13What is the Hygiene hypothesis?
- Immune stimulation by microbes protects against allergies
- Epidemiological data – Increase in Allergy
- Animal Models – T1DM, EAE, Asthma
- Increased atopy (Asthma) after anti-parasitic Rx
- Prevention of autoimmunity (Crohn’s) by infections
- Pro-biotics in pregnant women
- Mechanism – Th1/Th2 deviation, antigenic competition, immune regulation
What are the Genetic influences on the ‘allergic’ immune response?
Polygenic diseases Cytokine gene cluster IL3,5,9,13 IL12R; IL4R FceRI IFNg; TNF
NOT sufficient for disease
ONLY susceptibility
What are Susceptibility Genes for Allergic diseases?
Susceptibility genes for allergic disease.
Group 1: sensing the environment. The group of genes encodes molecules that directly modulate the effect of environmental risk factors for allergic disease. For example, genes such as TLR2, TLR4, and CD14, encoding components of the innate immune system, interact with levels of microbial exposure to alter the risk of allergic immune responses.71 Polymorphisms of glutathione-S-transferase genes have been shown to modulate the effect of exposures involving oxidant stress, such as tobacco smoke and air pollution on asthma susceptibility.
Group 2: barrier function. A high proportion of the novel genes identified for susceptibility to allergic disease through genome-wide linkage and association approaches have been shown to be expressed in the epithelium. This includes genes such as FLG,70 which directly affects dermal barrier function and is associated not only with increased risk of atopic dermatitis but also with increased atopic sensitization. Other susceptibility genes, such as ORMDL3/GSDML,34 PCDH1,24 and C11orf30,44 are also expressed in the epithelium and might have a role in possibly regulating epithelial barrier function.
Group 3: regulation of (atopic) inflammation. This group includes genes that regulate TH1/TH2 differentiation and effector function (eg, IL13, IL4RA, and STAT674; TBX21 [encoding T-box transcription factor]75; and GATA376), as well as genes such as IRAKM,77 PHF11,21 and UPAR23 that potentially regulate both atopic sensitization and the level inflammation that occurs at the end-organ location for allergic disease. This also includes the genes shown to regulate the level of blood eosinophilia (IL1RL1, IL33, MYB, and WDR36).41
Group 4: tissue response genes. This group includes genes that modulate the consequences of chronic inflammation (eg, airway remodeling), such as ADAM3317 and PDE4D,39 which are expressed in fibroblasts and smooth muscle, and COL29A1,25 encoding a novel collagen expressed in the skin linked to atopic dermatitis. Some genes can affect more than 1 disease component. For example, IL13 regulates both atopic sensitization through IgE isotype switching but also has direct effects on the airway epithelium and mesenchyme, promoting goblet cell metaplasia and fibroblast proliferation.14
What are allergens?
Antigens that initiate an IgE-mediated response
First encounter results in innate & IgM response
What is the Conventional Immune Response?
Allergen requires processing
Presentation to T cells & cytokine release
Results in delineation of T-helper subsets into different types
What is IgE?
- IgE comes from B cells but helped by Th2 cells (which release IL-4)
- IgE from plasma cells (differentiated B cells)
- IgE is the main factor in allergic response
What is the Role of the Th2 T cell?
- Generate Th2 type cytokines
- Role of Th2 cell- recruits innate inflamm cells (cause tissue damage)
- activate B cells to release IgE
What is Type I Allergic Response?
- IgE binds to Fc recep on sensitised mast cell
* Allergen cross links IgE antigens- THIS is what causes allergic response
What is IgE Mediated Allergic Response?
Immunopathogenesis
• IgE Ab mediated mast cell and basophil degranulation- release of preformed and de novo synthesized inflammatory mediators
Clinical features
• Fast onset (15-30 min)
• Wheal and flare (immediate phase of this reac)
• Late phase response- delayed reacs
Late phase response
• Eosinophils
• Central role for Th2 T cell
• Late phase- from cytokines & phospholipid reacs
What is Anaphylaxis?
- An acute, potentially life-threatening, IgE mediated systemic hypersensitivity reaction
- Stage 1- sensitization (no allergic response at this stge- immune response exposed to allergen, T cells making allergic antibodies)
- Stage 2- next time exposed- allergic antibosied made, IgE cross links
- Late phase
What is the Atopic Triad?
Atopic Triad- Asthma, Rhinitis, Eczema
• Mast cells in airways linings cause symptoms
• Have immediate symptoms in asthma & delayed
What is Nasal Allergic Inflammation?
- Allergic sensitization & allergic reaction in nasal mucosa= symptoms & functional alterations (e.g. nasal hyperresponsivness)
- FcεR1 = high-affinity Fc receptor for IgE
- GM-CSF = granulocyte-macrophage colony-stimulating factor
- ICAM-1 = intercellular adhesion molecule-1
- LFA-1 = lymphocyte function–associated antigen-1
- MIP-1α = macrophage inflammatory protein-1α
- NKA = neurokinin A
- PAF = platelet-activating factor
- TARC = thymus and activation-regulated chemokine
- Treg = regulatory T cell
- TxA2 = thromboxane A2
- VCAM-1 = vascular cell adhesion molecule-1
- VLA-4 = very late antigen-4
What is Rhinitis?
• Can be ALLERGIC/NON-ALLERGIC
• ALLERGIC= PERENNIAL (e.g. animals- exposed to throughout the yr House dust mite
Animal dander) or SEASONAL (hay fever related/ moulds)
Non-allergic: Vasomotor, Infective, Structural, Drugs, Hormonal, Polyps
• Blocked nose, runny nose - often with eye symptoms
• House dust mite, animal danders, pollens
• Treatment – Antihistamines & Nasal steroids (if don’t respond- can give immunotherapy)
What is Asthma?
- Disease of INFLAMMATION & HYPER-REACTIVITY of small airways
- In childhood - AERO-ALLERGIC stimuli - HOUSE DUST MITE key pathogenic importance
- IMMEDIATE symptoms are IgE-mediated
- DAMAGE TO AIRWAYS due to LATE PHASE RESPONSE (prostoglandins & leukotrienes)
- DAMAGED AIRWAYS ARE HYPER-REACTIVE to non-allergic stimuli e.g. fumes (get symptoms from non-specific symptoms not just allergn e.g. perfume- not an allergn but hyperreactive airways )
What is Atopic Dermatitis ?
- DERMATITIS – MANY DIFFERENT TYPES
- ATOPIC (inherited)
- CONTACT - ALLERGIC/NON-ALLERGIC
- CLINICALLY - Intense itching, blistering/weeping, cracking of skin
- HOUSE DUST MITE now thought to be MAJOR TRIGGER in atopic disease
- Topical Steroids & Moisturisers
What is the Interplay among the barrier, allergy, and pruritus ?
Interplay among the barrier, allergy, and pruritus as a trinity
• Itch- key component of pathogenesis
• Itch; disrupts barrier
• Cytokine can cause itch- treatments can target this
What is Sensitization and Acute Phase Response?
- Sensitization & Memory Induction
• Sensitization to allergens & development of specific B-cell and T-cell memory
• Allergen-specific T helper 2 (TH2) cells differentiation & clonal expansion= cytokine produc (interleukin-4 (IL-4) and IL-13)
• Cytokines induce Ig class switching to IgE & clonal expansion of naive & IgE+ memory B-cell pops
• IgE at surface of allergen-specific IgE+ B cells & other IgE-sensitized antigen-presenting cells facilitates antigen presentation.
• T-cell activation in the presence of IL-4 increases differentiation into TH2 cells. - Type 1 Hypersensitivity Reaction (IMMEDIATE phase of allergic reac)
• Crosslinking of mast-cell & basophil cell-surface FcRI (high-affinity recep for IgE)-bound IgE by allergens
• Leads to release of;
o Vasoactive amines (e.g. histamine)
o Lipid mediators (e.g. prostaglandin D)
o Platelet-activating factor
o Leukotriene C4 (LTC4), LTD4 & LTE4)
o Chemokines (CXC-chemokine ligand 8 (CXCL8), CXCL10, CC-chemokine ligand 2 (CCL2), CCL4 & CCL5)
o Other cytokines (such as IL-4, IL-5 and IL-13)
• And to the immediate symptoms of allergic disease. - Allergic Inflammation (LATE phase of allergic Reac)
• Allergen specific T cells (under influence of chemokines & other cytokines) migrate to sites of allergen exposure, reactivated & clonally expand
• Local IgE-facilitated antigen presentation by dendritic cells increases T-cell activation
• Local IgE produc in allergic rhinitis & asthma but NOT in allergic skin inflamm (e.g. atopic dermatitis)
• Eosinophils- one of main inflamm cells (up to 50% of cellular infiltrate) in asthmatic lungs but NOT in skin of those with atopic dermatitis
• TH1 cells make interferon- (IFN) & tumour-necrosis factor (TNF)= contrib to activation & apoptosis of keratinocytes (in skin), bronchial epithelial cells & pulmonary smooth-muscle cells.
Mast cells & basophils activation (release histamine, chemokines & other cytokines) also contrib to late-phase allergic reaction.
How do you diagnose allergies?
- History
- Specific IgE (>0.35 KuA/L)- TIME duration before symptoms
- Skin prick test (>3mm wheal)- put drop of allergen extract on skin, scratch skin & will see weal & flare response
- Intra-dermal test- (more invasive) inject allergen into intra-dermal space, see if size of bleb (mark you made when you have injected) increases
- Oral challenge test – Gold standard- take 1/8th of a peanut & keep doubling dose- see if they can tolerate 4 or 5 peanuts (if can not allergic)
- Basophil activation test- see if basophils change in surface proteins
- Component resolved diagnostics
- Immediate onset reacs- type 1 happens in few mins
- Can measure specific antigens to common allergens- In vitro test (take blood sample form patient)
- Take blood to see if antibodies against them- if are against parts of protin that are more stable- more severe reac
What is the Basophil Activation Test?
Principle of the basophil activation assay;
• Upon cross-linking of membrane-bound IgE, basophils upregulate expression of specific activation markers e.g.CD63, CD203c & expression of the inhibitory receptor CD300a
• Exact mechanisms causing basophil degranulation remain elusive, but phosphorylation of p38 MAPK pivotal role in cell activation
• Put allergen on basophil
What are the Advantages and Disadvantages of the Specific IgE test?
Advantages: Safe
Disadvantages: False negatives, False positives
What are the Advantages and Disadvantages of the Skin Prick Test?
Advantages: Quick, Patient satisfaction
Disadvantages: False negatives, False positives, Antihistamines, Slight risk
How do you treat allergies?
• Symptomatic
o Antihistamines, Steroids, Adrenaline (if severe life threatening reac- patients can carry these if reac can affect airways)
o Specific – Immunotherapy (Subcutaneous or Sublingual)
• Indications
o Life threatening reactions to Wasp & Bee sting
o Severe Hay fever
o Animal dander allergy
• Not helpful
o Multiple allergies don’t respond to immunotherapy as well
o Food allergy
o Allergic rashes – Eczema, Urticaria
What are the Mechanisms of Immunotherapy?
- Allergen-specific immunotherapy (SIT) improves quality of life of treated individuals & reduces symptoms of allergy & medication use.
- SIT; improved tolerance to allergen challenge, ↓ in immediate-phase and late-phase allergic inflamm, prevents development of new allergic sensitizations & ↓ progression of allergic rhinitis to asthma.
- SIT is disease modifying & duration of effect beyond the treatment period.
- SIT modifies cellular & humoral responses to allergen; ratio of T helper 1 (TH1) cytokines to TH2 cytokines increased & functional regulatory T cells induced.
- Interleukin-10 (IL-10) produc by monocytes, macrophages, B cells & T cells is increased
- The expression of transforming growth factor- (TGF) is increased & (with IL-10) TGF might contrib to regulatory T-cell function & immunoglobulin class switching to IgA, IgG1 and IgG4.
- These immunoglobulins compete with IgE for allergen binding, decreasing allergen capture & presentation by IgE in complex with high-affinity recep for IgE (FcRI) or low-affinity recep for IgE (FcRII).
- SIT also reduces mast cells and their ability to release mediators.
- Eosinophils and neutrophils recruitment to sites of allergen exposure is also reduced
What are adverse reactions to food?
• Major Food Allergens (if person thinks allergic to something go through list on this slide);
o Water soluble glycoproteins 10 - 60 kd
o COW’S MILK (more common in childhood- 80% don’t end up with this allergy)
o EGG
o LEGUMES – PEANUT (if in childhood usully don’t always have this allergy when older) ; SOYBEAN; TREE NUTS
o FISH
o CRUSTACEANS / MOLLUSCS
o CEREAL GRAINS (refrain from testing to wheat as the wheat specific IG often +ve)
• Common- food intolerance rather than food allergy
• Pharmacological effect of food not allergic reac e.g. heart beats faster after coffeee
• Lactose intolerance- lack lactose recep
• Allergies; can get allergy syndrome (e.g. eat fresh apple- react, but don’t reac to cooked apple as proteins more sensitive, & when gets to stomach acid breaks protein down so don’t get reaction below airways)
What are clinical manifestations of adverse reactions to food?
- Gastrointestinal: vomiting, diarrhoea, oral symptoms
- Respiratory (upper & lower): rhinitis, bronchospasm
- Cutaneous: urticaria, angioedema, role of food in atopic dermatitis unclear (rash for 2-3 wks unlikley is down to IgE sensitivity)
- Anaphylaxis
What are drug allergies?
- Cytotoxic- type II; hapten binds to protein on RBC- this combo recognised by immune system= haemolytic anaemia
- If no response to eczema treatment creams- patch test them to see what allergic to
- Chugg Strauss syndrome (serious)- don’t try testing them just tell them to avoid that drug
History Indication for the drug Detailed description of the reaction Time between drug intake and onset of symptoms Number of doses taken before onset
Management
Intradermal testing
Graded challenge
Desensitization
What is the innate immune system?
- Inflammation in target tissues (cells in tissues- respond to pathogens)
- Cells; macrophages, dendritic cells, mast cells, neutrophils, complement
- Pattern recognition against broad classes of antigen
- No memory
- No amplification
- Little regulation
- Fast response (hours – days)
- Short duration
What is the adaptive immune system?
- Cells circ through blood & coordinate responses
- Cells; T & B cells
- Highly specific (T and B cell receptors)- learn antigens that are foreign or not (memory)
- Strong memory and amplification component (e.g. vaccines, previous infection)
- Many regulatory mechanisms
- Slow response (days to weeks for initial exposure)
- Responses may last months - years
How are the innate and adaptive immune system related?
- Dendritic cells (innate) present antigen to T cells (adaptive)
- T cell cytokines & B cell antibodies activate innate cells to cause inflammation
- Innate immunity doesn’t adapt as well as adaptive immune system
- Macrophage presents to T cell then get adaptive response
- When T/b cells recognise foreign- they also active immune response (don’t work on their own)
What are Phagocytic cells?
- Neutrophils: eat and destroy pathogens (netosis- pus)
- Macrophages: also produce chemokines to attract other immune cells
- Dendritic cells (phagocytic): also present antigen to adaptive immune system
What are Histamine-producing cells?
- Mast cells, basophils, eosinophils: produce histamine and other chemokines and cytokines
- Vasodilatation, attract other immune cells
- Defence against parasites, wound healing but also allergy and anaphylaxis
What are Complement cells?
- Directly attacks pathogens via alternative and lectin pathways
- May be activated by adaptive immune system via antibodies
What are Cytokines?
Signal between different immune cells (e.g. innate to adaptive, adaptive to innate)
What are Chemokines?
Attract other immune cells to sites of inflammation (rather than signal)
What is Autoimmunity?
• = the ADAPTIVE immune system (learned response to antigen) recognises and targets the body’s own molecules, cells and tissues (instead of infectious agents and malignant cells)
• Main characteristics:
o T & B cells that recognise self antigens
o B cells and plasma cells that make autoantibodies against self antigens
o Inflammation in target cells, tissues and organs is secondary to actions of T cells, B cells and autoantibodies
• Autoimmunity is more about the learning of what is self & non-self
Immunological disruption: Adaptive immunity
Main cellular involvement: B and T cells
Antibody involvement: Autoantibodies present
Clinical features: Continuous progression
Conceptual understanding: Breaking of self-tolerance
Main genetic susceptibility: MHC class II associations and adaptive response genes
Therapy: Anti-B and T cell
Examples: Monogenic ALPS and IPEX, Polygenic RA and
SLE
Autoimmunity
• Theoretical concept
• Many cells of the immune system have capacity for autoimmune functions
• Overlap with normal immune functions such as anti-tumour immunity
Autoimmune Disease
• Distinct clinical entities
• Breakdown of self-tolerance
• Environmental factors acting on favorable genetic background
• Wide variety of pathogenic mechanisms between diseases
What is Autoinflammation?
• To distinguish from autoimmune diseases
• Main characteristics:
o seemingly spontaneous attacks of systemic inflammation (not learned T & B response)
o no demonstrable source of infection as precipitating cause
o absence of high-titre autoantibodies and antigen specific autoreactive T cells
o No evidence of auto-antigenic exposure
Immunological disruption: Innate Immunity
Main cellular involvement: Neutrophils, macrophages
Antibody involvement: Few or no autoantibodies
Clinical features: Recurrent, often seemingly unprovoked attacks
Conceptual understanding: Tissue-specific factors/danger signals
Main genetic susceptibility: Cytokine and bacterial sensing pathways
Therapy: Anti-cytokine (IL-1, TNF, IL-6)
Examples
Monogenic hereditary periodic fevers, polygenic Crohn’s disease, spondylarthropathies
What are the 3 Factors Involved in autoimmune disease?
- Genes can pre-dispose to certain disease e.g. certain MHC pre-disposes to rheumatoids but not just this as not born with disease
- Env trigger acts on genetic background to cause disease
- Immune regulation- certain regulation to help stop disease e.g. autoimmnity normally stops cancer (wipes out mutated cells before cause cancer) (regulation component can go wrong)
How do you develop central tolerance of B and T cells?
• Have central & peripheral types of tolerance
• Central tolerance;
o B cells- Bone marrow
o T cells- Thymus
• T cells in thymus as develop- get a T cell recep (recognises antigen- has variability; can recognise anything e.g. pathogen or self antigen), then process of –ve selection (tested against self-antigens, if recep picks up antigen delete it), then +ve selection for useful T cells (e.g. if recep doesn’t recognise self- is +vly selected)
• T cell can be useful if only recognise at low level- regulatory
• B cells go through similar process in bone marrow
What are the functions of MHC1 and H@ and what genes encode them?
Class II MHC Genes May Shape T Cell Repertoire: Predisposing to Autoimmunity • B cells & T cells variety to receptors they can express (not genetically linked) but can inherit types of molecules that leads to getting you autoimmune disease • MHC class I (on all nucleated cells in body- function is if there is something inside that tissue cells e.g. virus, gets presented on that surface) encoded by genes in HLA-A, HLA-B, HLA-C, On all nucleated cells, Presents antigen to CD8+ T cells • MHC class II (APCs e.g. skin infections, dendritic cell eats up antigen & takes it to lymph node to present to T cell in MHC) encoded by genes in HLA-DP, HLA-DQ, HLA-DR, On dedicated APCs, Presents antigen to CD4+ T cells • Have finite number of MHC types; each MHC subtype presents a certain antigen better than others e.g. if have a certain type of MHC might present self antigen better to T cells autoimmune (so usually have MHC class II association)
What are the consequences of a FOXP3 mutation?
FOXP3 mutation (gives regulatory cells)- failure to develop regulatory T cells – severe autoimmunity from birth
What are the consequences of a PTPNN22 mutation?
o PTPN22 mutations (genes that control how rapid activated T cells response is (how effective T cells are)- cause T cells to be activated more easily – stronger immune response in general
What are the epidemiological factors of autoimmunity?
• Sex (hormonal influence)- women»_space; men
• Age- autoimmunity more common in elderly (more exposed to diff env pathogen more likely to get autoimm disease)
• Sequestered Antigents
o May be recognised as foreign by the immune system (e.g. cell nucleus, eye, testis)
o Immune doesn’t react to certain cells as immune system never exposed to them so if happen to get exposed to them= autoimm
• Environmental triggers
o Infection
o Trauma-tissue damage
o smoking
What is Molecular mimicry ?
• Molecular mimicry e.g. in rheumatic fever antibodies against M protein of Streptococcus also happen to react against the glycoproteins of the heart valve cells (recep just happens to fit)
How can changes to Autoantigens May Cause Autoimmunity ?
- Citrullination of proteins make them more immunogenic (=rheumatoid arthritis)
- Self antigens start to be recognised as foreign as antigen itself changed- a.a. citrulline not encoded into genome so will never make it in protein but can sometimes switch places with arginine (which was coded- what smoking does)- makes protein look a bit foreign to body
- Tissue transglutamase alters gluten to help it bind to HLA-DQ (=coeliac disease)
- Failure to clear apoptotic debris increases availability of sequestered antigens inside the cell (=systemic lupus erythamatosus)
How do T cells stimulate autoimmunity?
• Th cell need antigen presented to them by APC with MHC
• T cell when sees antigen can;
o Differentiate into Th1 cell- make cytokines (signal to macrophages which make loads more cytokines)= inflammation
o Differentiate into Th2 cells= talk to B cells (cross talk)
• B cells differentiate into memory B cells & plasma cells= autoantibodies & cytokines=inflammation
• For process to stop; usually get rid of whatever causing it (e.g. infection)- but can’t do this in autoimmune disease (unless regulation)
Macrophages release inflammatory cytokines, this is also stimulated by T cells: APC binds to Th cell which causes Th1 to release inflammatory cytokines and Th2 to activate B cells causing auto antibody production
What is the Pathophysiology of autoimmune disorders?
• Autoreactive B cells and autoantibodies
o Directly cytotoxic
o Activation of complement
o Interfere with normal physiological function
• Autoreactive T cells
o Directly cytotoxic
o Inflammatory cytokine production
• General inflammation and end-organ damage
How do you group autoimmune disorders?
Organ Specific:
• Affect a single organ
• Autoimmunity restricted to autoantigens of that organ
• Overlap with other organ specific diseases
• Autoimmune thyroid disease is typical
Systemic
• Affect several organs simultaneously
• Autoimmunity associated with autoantigens found in most cells of body
• Overlap with other non-organ specific diseases
• Connective tissue diseases are typical
What are General Clinical Features of autoimmunity?
- More than 100 different diseases
- Can affect any organ of body
- Onset in middle age, old age
- More common common in the elderly and women
- Leads to loss of organ function
- Lifelong-chronic condition
- Characteristic exacerbation and remission
- Traditionally divided into organ specific or systemic
- Common for diseases to overlap
What is Autoimmune Thyroid Disease?
• Hashimotos thyroiditis (underactive thyroid)
o Destruction of thyroid follicles by autoimmune process
o Associated with autoantibodies (only in thyroid gland) to thyroglobulin & to thyroid peroxidase
o Leads to hypothyrodism
o 1st get hypEr as lots of thyroxine released but end up with hypo
o Inflamm & damage
• Grave’s disease
o Antibody mimics TSH- binds to TSH recep on thyroid galnd which stimulates recep which makes gland over active
o Inappropriate stimulation of thyroid gland by anti-TSH-autoantibody
o Leads to hyperthyroidism
o Graves- just antibody causes disease
What is the cause of Myasthenia Gravis?
- Acetylcholine usually stimulatess muscle contraction
- Myasthenia gravis- antibody against ACh receptors these antibodies block receptors so no acetylcholine stimulation therefore patients have decreased muscle activity
What is the cause of Pernicious Anaemia?
• Can’t absorb B12- as intrinsic factor can’t bind it as autoantibody blocks intrinsic factor (withoit binding to intrinsic factor Vit B12 cant be absorbed) , can get parathesia , fatigue
What is Lupus?
- Antinuclear antibodies against structures in cell nucleus=systemic autoimmune disease as cell nucleus everywhere in body
- Reason for butterfly rash- when go out in sun, UV light causes cells to undergo apoptosis, breaks down & contents of cell on outside of cell (in bleb), so the nuclear antigen visible to immune system (no longer hidden in cell)
- Non-organ specific- autoantibodies against antigens in the nuclus combine with their targets forming immune complexes in the circulation these can land anywhere in body (not necessarily where antigen came from e.g. skin) so can cause inflammation anywhere that’s why things like renal problems are a common side effect
What are Connective Tissue Diseases?
- Systemic lupus erythematosus
- Scleroderma
- Polymyositis
- Sjogrens syndrome
What are the General Principles of Diagnostic Testing ?
- Should use diagnostic tests to answer specific questions/ support clinical diagnosis NOT as screening tools
- Need to have an idea of what your testing for before ordering diagnostic test
- Their ability to correctly discriminate between health & disease is improved when they are used in the appropriate population
What is Sensitivity & Specificity? How are the calculated?
A: test positive and disease positive
B: test positive and disease negative
C: test negative and disease positive
D: test negative and disease negative
- Sensitivity [a/(a+c)]- True positive: how good the test is in identifying people WITH the disease (ability to pick up affected individuals)
- Specificity [d/(c+d)]- True negative: meausure of how good the test is in correctly defining people WITHOUT the disease
- Low specificity if test also picking up people without disease
- Positive predictive value [a/(a+b)]-The proportion of people with a positive test who have the target disorder
- Negative predictive value [d/(c+d)]- The proportion of people with a negative test who do not have the target disorder.
What are the different types of autoimmune diagnostic tests?
- Non specific- Inflammatory markers
* Disease specific- Autoantibody testing, HLA typing
