Exam 2 Flashcards
What is amyloidosis
Disease where an abnormal protein (some cases derived from Igs) deposits in tissues
Besides timing, what is the difference between adaptive and innate immunity
Adaptive can respond to other foreign substances besides just microbes
What are the major components of innate immunity
Epithelia (blocks entry), NK cells, dendritic cells, phagocytic cells, complement system
What do epithelial cells do to prevent entry of microbes
Produce antimicrobial molecules (defensins), lymphocytes located in epithelia combat microbes
What do natural killers provide defense against
Viruses and intracellular bacteria
Which complement pathways are used in innate immunity
Alternative and lectin
What other proteins are involved in innate immunity
CRP, mannose-binding lectin, lung surfactant
What recognizes PAMPs and DAMPS
Pattern recognition receptors
What are pattern recognition receptors found
Plasma membrane (extracellular microbes), endosomes (ingested), and cytosolic receptors (intracellular)
Where are TLRs found?
Plasma membrane and endosomes vesicles
What pathway do TLRs activate
NFkB which stimulates the synthesis and secretion of cytokines and expression of adhesion molecules AND interferon regulatory factors, which simtulate the production of antiviral cytokines (type I IFN)
What is NOD-like receptor
Recognizes products of necrotic cells, ion disturbances, and some microbial products; signal via inflammasome; gain of function of this receptor results in periodic fever syndrome (called autoinflammatory syndrome) -> treat with IL-1 antagonists; also involved in gout (recognizes urate crystals), obesity-associ T2DM (detects lipids) , and atherosclerosis (cholesterol crystals)
What are C-type lectin receptors
Expressed on plasma membrane of macrophages and dendritic cells; detect fungal glycans (illicit response to fungi)
What are RIG-like receptors
Located in cytosol, detect nucleus acids of viruses and replicate in cytoplasm of infected cell; stimulate production of antiviral cytokines
What do GPCRs on neutrophils and macrophages do?
Recognize short bacterial peptides containing N-formylmethionyl residues; stimulates chemotactic responses
What do mannose receptors do
Recognize mannose on microbes and induce phagocytosis of microbes
How does the innate immune system provide defense
Inflammation and antiviral defense (type I IFN act on infected and I infected cells and act on enzymes to degrade viral nucleus acid and inhibit viral replication)
What are the types of adaptive immunity
Humoral: against extracellular microbes and their toxins (mediated by B cells and abs)
Cell-mediated: against intracellular microbes (mediated by T cells)
What are effector and memory cells
Lymphocytes that have come into contact with their antigen
What functions do B cells ultimately have on microbes
Neutralization of microbes, phagocytosis, compliment activation
What is clonal selection
Lymphocytes express a receptor specific for an antigen -> antigens will specifically activate the antigen specific cell; all clones express same receptor
How is antigen receptor diversity generated
Somatic recombination of genes that encode for the receptor protein during maturation in the thymus and bone marrow; mediated by RAG-1 and 2 (recombination activating genes) -> inherited defects in RAG causes inability to generate mature lymphocytes
What can be a marker for T and B cell lineage
Presence of recombined TCR or Ig genes; only cells that recombine germline antigen receptor genes
What can be used to detect tumors derived from lymphocytes
Analysis of antigen receptor gene rearrangements (since each T or B cell and clonal progeny have unique DNA rearrangement)
What does the alpha beta TCR recognize
Peptide antigens presented by MHC molecules
What is the TCR linked to
Six polypeptide chains which form CD3 complex and chain dimer (identical in all T cells); involved in transcription of signals into the T cell
What does the gamma delta TCR recognize
Peptides, lipids, nd small molecules without presentation by MHC; tend to aggregate at epithelial surfaces (skin and mucosa of GI/GU tracts); sentinels that protect from microbes trying to enter through epithelia
What are NK-T cells
Recognize glycolipids displayed by MHC-like molecule CD1; function not well defined
What are CD4 and CD8 expressed on
Alpha beta T cells
What do integrins do in the T cell response
Promote attachement of T cells to APCs
What is located on the surface of all mature, naive B cells
IgM and IgD (antigen binding component of B cell receptor complex)
What happens to B cells after stimulation by antigen
Develop into plasma cells (make abs); also in blood called plasmoblasts
What makes up the B cell receptor complex
Heterodimer of Igalpha (CD79a) and beta (CD79b) -> invariant; signal transduction; also contains type 2 complement receptor (CR2/CD21) -> recognizes complement products; CD40 (receives signals from helper T cells); *CR2 used by Epstein Barr virus to enter and infect B cells
Where are dendritic cells located
Under epithelia and interstitia of all tissues
What are langerhans cells
Immature dendritic cells located within the epidermis
What are follicular dendritic cells
Dendritic cells located in germinal centers in the spleen and LN; have Fc receptor for IgG and receptor for C3b; can trap antigen bound to abs or complement; plays a role in humoral response by presenting antigens to B cells and selecting the B cells that have the highest affinity for the antigen
What are the general roles of macrophages in adaptive immunity
Present peptides to T cells, effector cells in cell mediated immunity (t cells activate macrophages to make them better at killing ingested microbes), and effector cells in humoral immunity (destroy opsonized microbes)
What is the function of NK cells
Destroy irreversibly stressed cells (virus infected and tumor); do not express TCRs or Ig, have azurophilic granules; can kill without prior exposure; express CD16 and CD56 (markers); CD16 is a Fc receptor for IgG (can lyse IgG coated targets - called antibody dependent cell-mediated cytotoxicity)
How is the functional activity of NK cells controlled
Activating receptors: NKG2D family -> recognize surface molecules induced by stress Inhibitory receptors: recognize self class I MHC molecules (expressed on all healthy cells)
Which ILs stimulate the proliferation of NK cells
IL 2 and 15
What is the effect of IL-12 on NK cells
Activates killing and secretion of IFN-y
What are innate lymphoid cells
Lack TCRs but produce cytokines similar to that made by Tcells; NK cells are an example; different subsets produce IL-5,17,22 and IFN-y; function as early defense, stress surveilance, and shaping adaptive response. By providing cytokines that influence differentiation of T cells
What are generative lymphoid organs
Where T and B cells mature; also called primary or central
What is the function of the spleen
Blood born antigens are trapped here by dendritic cells and macrophages
What are the cutaneous and mucosal lymphoid systems
Cutaneous: located under epithelia of skin
Mucosal: located in GI and respirator tracts (pharyngeal tonsils and Peyers patches)
Where are B and T cells located in LN
B cells: follicles in the cortex; if recently responsed to an antigen, may have germinal center; contains follicular dendritic cells
T cells: paracortex; contains dendritic cells
Where are T cells and B cells located in the spleen
T cells: perioarteriolar lymphoid sheaths surrounding small arterioles
B cells: follicles
Where are the genes that encode for HLA molecules located
Chromosome 6
Describe the structure of MHC I molecules
Heterodimer of polymorphic alpha (heavy chain) linked to nonpolymorphic protein called beta2 microglobulin; alpha chains encoded by HLA-A,B, and C; extracellular region of alpha chain divided into three domains; alpha1 and 2 form a cleft for peptide binding (AA resides line the sides - explains why different class I alleles bind different peptides)
What do Class I MHC molecules display
Peptides derived from proteins (viral and tumor antigens) located in cytoplasm and produced in the cell
Describe how proteins are displayed by class I MHC
Cytoplasmic proteins degraded in proteasomes and transported to ER where they bind to MHC I molecules; associate with beta2microglobulin that is transported to surface
What does the alpha 3 portion of the class I MHC molecule bind to
CD8
Describe the structure of class II MHC molecules
Heterodimer of alpha and beta chain (both polymorphic); extracellular portion has alpha 1, alpha 2, beta 1, and beta 2; cleft formed by alpha 1 and beta 1 (this portion is where most differ)
What do class II MHC molecules present
Antigens internalized into vesicles, typically derived from extracellular microbes and soluble proteins
Describe how class II molecules present their antigen
Proteins are proteolytically digested in endosomes or lysosomes; peptides associate with class II heterodimers in vesicles and transported to surface
What does the class II beta 2 domain bind to
CD4
Besides MHC genes, what else does the MHC locus encode for
TNF, complement components, lymphotoxin
Which cytokines are released in innate immunity
TNF, IL-1,12,type I IFNs, IFN-y and chemokines
What is the main producer of cytokines in adaptive immune responses
CD4 T cells; IL-2,4,5,17, IFN-y, TGF beta, IL-10
What are colony stimulating factors produced by
Marrow stromal cells, T lymphocytes, macrophages; ex: GM-CSF and IL-7
What can be used to treat rheumatoid arthritis
TNF antagonist
What is the difference between what T cells can recognize versus B cells
T cells just peptides
B cells: proteins, polysaccharides, and lipids
What is an adjuvant
Given with protein antigen in vaccines; activates innate response; activates APCs to express costimulators and secrete cytokines that stimulate proliferation and differentiation of T cells; principal costimulators are B7 proteins (CD80 and 86) on APCs, recognized by CD28 on naive T cells
What is “signal 2”
Triggered by costimulators; ensures that adaptive immune response is only induced by microbes; immune responses to tumors, signal 2 can be DAMPs from necrotic cells
What does CD40 ligand do
Expressed on activated T cells; binds to CD40 on macrophages and B cells and activates them
What do TH2 cells secrete
IL-4 (B cells differentiate into IgE)
IL-5 (recruits eosinophils)
What are T-dependent antibody response
Some ab responses to protein antigens require T cells; B cells ingest protein and present them to T cells via Class II MHC; T cells stimulate B cells
What ab do polysaccharides and lipids cause the release of
IgM
What ab do protein antigens cause the release of
Different classes IgG, IgA, IgE; isotope switching (induced by IFN-y, and IL-4); helper T cells also stimulate production of abs with high affinities for antigens (called affinity maturation)
Where do isotope switching and affinity maturation occur
Germinal centers, which are formed by proliferating B cells
What are follicular helper T cells
Helper T cells that migrate into the germinal centers to stimulate isotype switching and affinity maturation
Which abs opsonize
IgG
Where is IgA secreted
From mucosal epithelia in respiratory and GI tract
What ab is actively transported across the placenta
IgG; protect newborn
What happens to the effector lymphocytes after the microbe has been eliminated
Most die by apoptosis
Which cytokines induce the differentiation of Th1,2,and 17
Th1: IFN-y and IL-12
Th2: IL-4
Th17: TGF beta, IL-6, IL-1, IL-23
What does Th1 cells trigger
Macrophages activation and IgG ab production
What is the Th1 role in diseases
autoimmune and chronic inflammatory diseases (IBD, psoriasis, granulomatous inflammation)
What is the role of Th2 in disease
Allergies
What is the role of Th17 in disease
Autoimmune and chronic inflammatory diseases (IBD, psoriasis, MS)
Which part of the Ig switches in isotype switching
Heavy chain
What are immediate (type I) hypersensitivity reactions
Caused by Th2 cells, IgE abs, mast cells and other leukocytes
What are type II hypersensitivity disorders
Ab mediated; secreted IgG and IgM abs injure cells by promoting their phagocytosis or lysis and injure cells by inducing inflammation; abs can also interfere with cellular function and cause disease without injury
What are type III hypersensitivity reactions
Immune-complex mediated; IgG and IgM abs bind antigens in circulation and deposit on tissues, inducing inflammation; leukocytes are recruited and produce tissue damage by release of lysosomal enzymes and generation of free radicals; causes necrotizing vasculitis (fibrinoid necrosis)
What are type IV hypersensitivity reactions
Cell-mediated immune disorders; sensitized T lymphocytes (Th1,17, and CTLS) cause injury; causes perivascular cellular infiltrates, edema, granuloma ormation
What are the phases of Type I hypersensitivity reaction
Immediate reaction: vasodilation, vascular leakage, and depending on location, smooth m spasm or glandular secretions; subside in a few hours
Late phase reaction: (common in allergic rhinitis and bronchial asthma) sets in 2 to 24 hours later and can last for several days; characterized by infiltration of eosinophils, neutrophils, basophils, monocytes, and CD4 T cells; mucosal epithelial cell damage
What is an example of Type II hypersensitivity reaction
Autoimmune hemolytic anemia, Goodpasture syndrome
What are examples of type III hypersensitivity
Lupus, glomerulonephritis, serum sickness, Arthur’s reaction
What are examples of type IV hypersensitivity
Contact dermatitis, MS, T1DM, TB
What is the role of IL-13 in type I hypersensitivity
Enhances IgE production and acts on epithelial cells to stimulate mucus secretion
Where are mast cells derived from
Bone marrow
Where are mast cells abundantly found
Near BV and nerves and in subepihtlial tissues; explains why local immediate hypersensitivity reactions occurs at these sites
What are some things that induce mast cell secretion
IL-8, codeine, morphine, adenosine, mellitin (bee venom), head, cold, sunlight
How are basophils similar to mast cells
Have Fc IgE receptor and cytoplasmic granules; different because not present in tissues -> circulate blood in small numbers
What happens when an antigen binds to a sensitized mast cell
Antigen binds to and cross links adjacent IgE abs; underlying Fce brough together which activates signal transduction pathways from cytoplasmic portion of receptors
What are the preformed mediators in mast cells
Vasoactive amines (histamine), enzymes (neutral proteases: Chymase and tryptase and acid hydrolases -> cause tissue damage and lead to generation of kinins and complement); proteoglycans: heparin and chondroitin sulfate (package and store amines in granules)
What are the secondary mediators found in mast cells
Lipid mediators (leukotrienes, prostaglandin D2, and PAF): reactions in cell membrane activate phospholipase A2 to produce AA; *PAF not derived from AA -> causes platelet aggregation, release of histamine, bronchospasm, increased permeability, and vasodilation Cytokines: TNF, IL-1, chemokines (leukocyte recruitment -> late phase reaction), IL-4 (amplifies Th2 response)
What is the immediate type I hypersensitivity reaction characterized by
Edema, mucus secretion, smooth m spasm
What is the late phase reaction believed to be involved in
Allergic asthma; treatment requires broad spectrum of anti inflammatory drugs such as steroids instead of anti-histamine drugs which would just target the immediate reaction (ie: use for hay fever/allergic rhinitis)
What is atopy
Increased propensity to develop immediate hypersensitivity reactions
What are some characteristics that atopic individuals tend to h ave
Higher serum IgE levels and more IL-4 producing Th2 cells; positive family history of allergy
Genes encoded on what chromosome are linked to familial predisposition to allergies
5q31; include genes that encode for IL-3,4,5,9,13, and GM-CSF
Besides genetics, what is important in the development of allergies
Environmental factors
What is nonatopic allergy
Immediate hypersensitivy reaction triggered b y non-antigenic stimuli such as temperature extremes and exercise; no Th2 or IgE; mast cells are abnormally sensitive to activation
What has the increase in presence of allergic diseases been linked to
Decrease in infections during early life; hygiene hypothesis -> early exposure to microbial antigens educates the immune system so that subsequent pathological responses against common allergens are prevented
What occurs during systemic anaphylaxis
Within minutes: itching, hives and skin erythema, followed by contraction of respiratory bronchioles, then laryngeal edema, vomiting, abdominal cramps, diarrhea, and laryngeal obstruction flow
What is antibody-dependent cellular cytotoxicity
Cells that are coated with IgG ab are killed by NK and macrophages which bind to the starter via their Fc fragment of IgG; cell lysis occurs
What kind of hypersensitivity is transfusion reactions
II; cells from incompatible donor react with an are opsonized by preformed ab in the host
What kind of hypersensitivity reaction is hemolytic disease of the newborn (erythroblastosis fetalis)
II; IgG anti-Erythrocyte abs from the other cross the placenta and destroy fetal RBCs
What is autoimmune hemolytic anemia, agranulocytosis and thrombocytopenia
Individuals produce abs to their own blood cells -> type II
What are drug reactions, where the drug acts as a happen
Drug binds to the plasma membrane of RBCs -> abs produced agains the drug-protein complex; type II
What happens when ab deposit in fixed tissues
Ie: basement membrane and extracellular matrix; resultant injury due to inflammation; activate complement which recruits leukocytes, which are activated by their C3b and Fc receptors; this releases production of lysosomal enzymes (proteases that can digest basement membrane) and ROS; mechanism responsible in glomerulonephritis and vascular rejection in organ grafts; type II
How can type II hypersensitivity impair cellular function
Abs to cell surface receptors; Ie: myasthenia gravis -> abs to Ach receptors in motor end plates of skeletal mm causes m weakness; also, Graves’ disease -> ab to TSH receptor activates the receptor and results in hyperthyroidism
What is the target antigen in autoimmune thrombocytopenia purpura
Platelet membrane proteins (GpIIb:IIIa); causes opsonization of phagocytosis of platelets -> bleeding
What is pemphigus vulgaris
Targeted antigen -> proteins in intercellular junctions of epidermal cells (cadherin); causes ab mediated activation of proteases and disruption of cellular adhesions -> skin vesicles (Bullae) form (type II)
What is targeted in goodpasture syndrome
Noncollagenous protein in basement membrane of kidney glomeruli and lung alveoli; causes complement and Fc receptor mediated inflammation -> nephritis and lung hemorrhage (type II)
What is the target antigen in acute rheumatic fever
Streptococcal cell wall antigen; ab cross reacts with myocardial antigen -> inflammation and macrophage activation -> myocarditis and arthritis
What kind of hypersensitivity reaction is type II diabetes
II; targets insulin receptor -> ab inhibits binding of insulin
What is targeted in pernicious anemia
Intrinsic factor of gastric parietal cells -> causes neutralization of IF which causes decreased absorption of B12 -> abnormal erythropoiesis and anemia
What are common characteristics of type III (immune complex mediated) hypersensitivity
Systemic, preferentially involving kidney, joints, and small vessels
What are the phases of systemic immune compiles disease
- Formation of immune complexes: intro of a protein triggers production of abs, typically about a week after injection; complexes form
- deposition of complexes (medium sized with slight antigen excess are most pathogenic); organs where blood is filtered at high pressure to form other fluid (urine and synovial fluid) are where they become concentrated and deposit
- inflammation and tissue injury: imitation acute inflammatory reaction (approx 10 days after administration); causes fever, urticaria, joint pains (arthralgias), LN enlargement and proteinuria
Which abs are involved in immune complex disorders
IgG and IgM
How do we know that complement proteins are significant in type III hypersensitivity
Consumption of complement leads to decrease in serum C3 levels
What is the morphology of immune complex injury
Acute vasculitis, necrosis of vessel wall and intense neutrophilic infiltration; *fibrinoid necrosis (appears smudgy eosinophilic areas)
What is the arthus reaction
Localized area of tissue necrosis caused by acute immune complex vasculitis in the skin; can be produced by injection of an antigen in a previously immunized animal that contains circulating abs for that antigen
What is the prototype of CD4 T cell mediated inflammation
Delayed type hypersensitivity: tissue reaction to immune individuals; administration of an antigen results in cutaneous reaction within 24-48 hours (delayed)
What are the stages of CD4 mediated inflammation
Activation of T cells: naive CD4 T cells recognize antigen and produce IL2; if APC produces IL-12 -> Th1; if IL-1,6,or 23 then Th17 Responses of effector cells: repeat exposure to antigen, TH1 secretes IFN-y; causes macrophages to express more class II MHC which facilitates further presentation, secrete TNF, IL1 and chemokines to promote inflammation and IL12 to amplify Th1 response; Th17 produce IL-17 and 22 -> neutrophils and monocytes
What are examples of T cell mediated diseases
Rheumatoid arthritis, MS, T1DM, IBD, psoriasis, contact sensitivity
What is the target antigen in MS
Myelin; inflammation by Th1 and 17; myelin destruction by macrophages
What is tuberculin reaction an example of
CD4 mediated inflammatory reaction (delayed type hypersensitivity)
Describe what the tuberculin reaction is
Intracutaneous injection of purified protein derivative (PPD) containing the antigen of tubercle bascillus; in a previously sensitized individual, injection causes redness and induration of the site in 8-12 hours, peak in 24-72 hours and then subsides
Morphologically, what are DTH reactions characterized by
CD4 T cells and macrophages accumulated around venules, producing perivascular cuffing; in fully developed lesions -> venules show endothelial hypertrophy (cytosine mediated endothelial activation)
What are granulomatous inflammation associated with
Strong Th1 cell activation and high levels of IFN-y
How does contact dermatitis work
Environmental chemical binds to and modifies some self proteins -> peptides derived from these modified proteins are recognized by T cells and elicit the reaction; chemicals can also modify HLA molecules, making them appear foreign; same mechanism used for most drug reactions
What is an example of CD8 T cell mediated cytotoxicity disease
T1DM, graft rejection
What are the requirements that must be met to diagnose an autoimmune disorder
Presence of an immune reaction specific for some self antigen or self tissue, evidence that such a reaction is not secondary to tissue damage, and the absence of another well-defined cause of the disease
What are the organ specific autoimmune diseases mediated by abs
Autoimmune Hemolytic anemia, thrombocytopenia, atrophic gastritis of pernicious anemia, myasthenia gravis, Graves’ disease, good pasture syndrome
What the organ specific autoimmune diseases. Mediated by T cells
T1DM, MS
What are the systemic autoimmune diseases mediated by abs
SLE
What are the systemic autoimmune diseases mediated by T cells
Rheumatoid arthritis, sjogren syndrome, and systemic sclerosis (scleroderma)
What is central tolerance
Immature self reactive T and B clones that recognize self antigens during their maturation in generative lymphoid organs are killed
Describe the central tolerance process for T cells
When immature T cells recognize a self antigenmany die by apoptosis (negative selection or deletion); AIRE (autoimmune regulator) stimulates expression of peripheral tissue-restricted self ags in the thymus (mutation causes autoimmune polyendocrinopathy); some develop into Treg cells
Describe central tolerance in B cells
When B cells recognize self antigens, many of the cells reactivate the machinery for antigen receptor gene rearrangement and begin to express new antigen receptors (receptor editing), if this does not occur, they undergo apoptosis
What is anergy
Self reactive T cells are rendered unresponsive; costimulators (B7) are weakly expressed on normal tissues; thus the self reactive T cells will not have the costimulation needed and become anergic; also,these cells receive inhibitory signals from CTLA4 (which has a higher affinity for B7 and are therefore more likely to bind)
What are antibodies that block CTLA-4 and PD-1 used for
Treat tumor immunotherapy; promotes response against tumors
How does anergy affect B cells
If B cells encounter self antigen in peripheral tissues (especially in absence of T helper cells), B cells become usable to response and may be excluded from lymphoid follicles (resulting in their death)
What are the best defined T reg cells
CD4 cells that express high levels of CD25, the alpha chain of the IL-2 receptor, and FOXP3
What does mutation of FOXP3 cause in humans
IPEX (Immune dysregulation polyendocrinopathy, enteropathy, X-linked)
Which IL is essential for maintenance of T reg cells
IL-2
How to Treg cells suppress immune responses
Secrete IL-10 and TGFbeta, also express CTLA-4, which may bind to B7 on APCs and reduce the amount of B7 that can bind to CD28
How do self reactive T cells die by apoptosis
If T cells recognize a self antigen, they express a pro-apoptotic member of BCL family, called Bim without anti apoptotic members (antiapoptotic require full lymphocyte signaling to be activated); Bim triggers apoptosis by mitochondrial pathway; also CD4+ and B cells can die by Fas-FasL apoptosis (both are expressed on self reactive cells)
A mutation in FAS causes what disease
autoimmune lymphoproliferative syndrome (ALPS)
What are the immune privileged sites
Brain, eye, testis; antigens do not communicate with blood or lymph; therefore if antigens released by trauma, causes prolonged immune response; mechanism for post-traumatic orchitis and uveitis
What is inheritance of HLA-B27 linked to
Ankylosing spondylitis
What is inheritence of DQA1 and DQB1 associated with
Celiac disease
What is inheritence of DRB1 associated with
MS, T1DM, rheumatoid arthritis and SLE
What are polymorphisms in PTPN22 associated with
Encodes a protein tyrosine phosphatase; associated with T1DM, rheumatoid arthritis, and other autoimmune dz *gene most frequently implicated in autoimmunity; encodes for a phosphatase that is functionally defective and cannot control activity of RTK (excessive lymphocyte activation)
What are polymorphisms of NOD2 associated with
Crohn dz; cytoplasmic receptor; dz variant is ineffective at sensing gut microbes, including commensal bacteria, which results in entry of and chronic inflammatory responses against these organisms
What are polymorphisms in the IL-2 receptor (CD25) and IL-7 receptor alpha chains associated with
MS
What does a knockout of the IgG Fc receptor on B cells cause
Autoimmunity; binding of IgG/ab complexes to the Fc receptor on B cells turns the B cells off; thus, B cells can no longer be controlled d
How do infections trigger autoimmune responses
Infections upregulate the expression of costimulators on APCs (breakdown of anergy b/c no self reactive T cells can react); also microbes can express antigens that have the same AA sequences as self antigens (molecular mimicry)
What is an example of molecular mimicry
Rheumatic heart disease; abs against strep cross react with myocardial proteins and cause myocarditis
How do Epstein Barr virus and HIV influence autoimmune reactions
Stimulate polyclonal B cell. Activation, which can result in auto-ab production
How can infections protect against some autoimmune diseases
Infections promote low level IL-2 production which maintains T reg cells
What role does IL23R play in autoimmune disease
Associated wtih IBD, psoriasis, and akylosing spondylitis; receptor for IL-23 (induced by Th17); alters differentiation of CD4 to Th17 effector cells
What is epitope spreading
An immune response against one self antigen cases tissue damage, releasing other antigens, resulting in activation of lymphocytes by these newly encountered epitopes
In T1DM, what kind of autoimmune reactions is involved in killing the beta cells
CD8 CTLs
Are abs or T cells involved in rheumatoid arthritis
Both
What do systemic autoimmune diseases tend to target
Blood vessels and connective tissue; therefore called collagen vascular diseases or connective tissue diseases
Who is most susceptible to SLE
Women between the ages of 17-55, blacks and Hispanics; however, can manifest at any age
What are the categories of antinuclear antibodies
Abs to DNA, abs to histones, abs to non histone proteins bound to RNA, and abs to nucleolar antigens
What is the method used to detect ANAs
Indirect immunofluorescence; can identify abs bound to a variety of nuclear antigens (DNA, RNA, proteins - called generic ANAs); pattern of fluorescence suggests type of ab present in patients serum
What are the listed criteria for SLE
Malar rash, discoid rash, photosenstivity, oral ulcers, arthritis, serositis, renal disorder, neurological disorder, hematologic disorder, immunologic disorder, antinuclear ab
What is a malar rash
Flat or raised over malar eminences, tends to spare nasolabial folds
What is a discoid rash
Erythematous raised patches with adherent keratitic scaling and follicular plugging; atrophic scarring can occur in older lesions
What is the arthritis criteria for SLE
Nonerosive arthritis involving 2 or more peripheral joints, characterized by tenderness, swelling, or effusion
What is the renal disorder criteria for SLE
Persistent proteinuria >.5 g/dL or cellular casts (RBC, hemoglobin, granular, tubular or mixed)
What is involved in the neurological criteria for SLE
Seizures in the absence of offending drugs or known metabolic derangement (ketoacidosis, uremia, or electrolyte imbalances) or psychosis in the absence of offending drugs or known metabolic derangements
What is involved in the hematologic criteria for SLE
Hemolytic anemia with reticulocytosis or leukopenia, lymphopenia, or thrombocytopenia on two or more occasions in the absence of offending drugs
What are the basic patterns displayed in indirect immunofluorescence when testing for ANAs
- Homogeneous or diffuse nuclear staining: abs to chromatin, histones, and dsDNA
- Rim or peripheral staining: abs to dsDNA and nuclear envelope proteins
- Speckled pattern: *most common so least specific; abs to non-DNA nuclear constituents such as SM antigen, ribonucleoprotein, and SS-A/B reactive antigens
- Nucleolar pattern: presence of few discrete spots within nucleus; abs to RNA *reported most often in patients with systemic sclerosis
- Centromeric pattern: abs to centromeres; also seen in systemic sclerosis
Abs to what are virtually diagnostic of SLE
dsDNA and smith antigen (speckled pattern and homogenous)
What are the targets of the antiphospholipid abs in SLE
Prothrombin, annexin V, beta2 glycoprotein I, protein S, and protein C
What does the ab to phospholipid beta2 glycoprotein also bind to
Cardiolipin antigen -> used for syphilis testing
Which clotting test do the abs present in lupus alter
PTT in vitro (lupus anticoagulant); but in vivo, actually cause hypercoaguability
What disease feature is linked to abs to dsDNA in SLE
Nephritis; specific for SLE
What disease feature are abs to SS-A (Ro) and SS-B (La) linked to in SLE
Congenital heart block, neonatal lupus
Abs to what are associated with systemic sclerosis
- DNA topoisomerase I (linked to diffuse skin and lung disease; specific for systemic sclerosis)
- Centromeric proteins (CENPs) ABC (linked to skin disease, ischemic digit loss, pulm HTN)
- RNA polymerase III (linked to acute onset, scleroderma renal crisis, cancer)
Abs to what are linked to Sjogren syndrome
SS-A/B
Abs to what are associated with autoimmune myositis
- Histidyl aminoacyl-tRNA synthetase, Jo1 (linked to interstitial lung dz, Raynaud phenomenon)
- Mi-2 nuclear antigen (linked to dermatomyositis, skin rash)
- MDA5 (cytoplasmic receptor for viral RNA) - linked to vascular skin lesions, interstitial lung dz
- TIF1-y nuclear protein (linked to dermatomyositis, cancer)
Abs to what are linked to rheumatoid arthritis
CCP (cyclic citrullinated peptides): specific for RA
Rheumatoid factor
Alleles of the HLA-DQ locus have been linked to production of abs against what
DsDNA, smith, and phospholipids
What is the involvement of complement in SLE
May have inherited deficiencies in early complement (C2,4, or C1q); lack of complement can impair removal of circulating immune complexes by phagocytes -> this favors tissue deposition; deficiency in C1q causes defective phagocytic clearance of apoptotic cells
Are the abs produced in SLE T cell dependent or independent
Dependent; produced in germinal centers; increased number of follicular helper T cells found in blood of SLE patients
What is the role of type I IFN in SLE
Lymphocytes activation; high levels of circulating type I IFN correlates with disease severity; type I IFNs are antiviral cytokines normally produced by innate immunity (in SLE could be caused by nuclear DNA binding to TLRs and causing dendritic cells to produce IFN)
What is BAFF
TNF family member that promotes survival of B cells; in some SLE patients, increased BAFF has been detected
How does exposure to UV light relate to SLE
May induce apoptosis and alter DNA in such a way that it becomes immunogenic (enhances recognition by TLRs); can also stimulate keratinocytes to produce IL-1
Which drugs can induce SLE-like response
Hydralizine, procainamide, isoniazid, and D-penicillamine
In SLE, what do auto-abs to RBC, WBC, an platelets do
Opsonize them and promote their phagocytosis and lysis
What are LE cells
Cells that have engulfed denatured nucleus of another cell; present in lupus (as well as pericardial or pleural effusions)
What does SLE do to blood vessels
Acute necrotizing vasculitis involving capillaries, small arteries, and arterioles can be present in any tissue; characterized by fibrinoid deposits; chronically, undergo vessel thickening and narrowing
Where do the immune complexes generally deposit in the kidney in SLE
Mesangium, basement membrane
What are the six patterns of glomerular disease found in SLE
Minimal mesangial lupus nephritis, mesangial proliferative, focal, diffuse, membraneous, advanced sclerosing *can advance to other stages; class I least common, class IV most common
What is minimal mesangial lupus nephritis
Class I: characterized b y immune complex deposition in the mesangium, identified by immunofluorescence and EM, but without structural changes by light microscopy
What is mesangial proliferative lupus nephritis
Class II: characterized by mesangial cell proliferation, accompanied by accumulation of mesangial matrix and granular mesangial deposits of Ig and complement without involvement of glomerular capillaries
What is focal lupus nephritis
Class III: involvement of few than 50% of all glomeruli; can be segmental (only portion of glomeruli affected) or global (entire glomerulus); affected glomeruli exhibit swelling and proliferation of endothelial and mesangial cells associated with leukocyte accumulation, capillary necrosis, and hyaline thrombi; often extracapillary proliferation and focal necrosis and crescent formation; clinical presentation can range from mild hematuria and proteinuria to acute renal insufficiency; red cast cells common; can heal or progress
What is diffuse lupus nephritis
Class IV: *most common and severe; lesions similar to class III; half or more of glomeruli are affected; may be segmental or global (IV-s or IV-G); proliferation of endothelial, mesangial and epithelial cells (produces cellular crescents that fill Bowmans space); subendothelial immune complex deposition creates a wire loop (circumferential thickening of capillary Wall seen on light microscopy); immune complexes detected by EM and immunofluorescence; can progress to scarring; usually symptomatic (hematuria and proteinuria; also HTN common)
What is membraneous lupus nephritis
Class V: diffuse thickening of capillary walls due to deposition of subepithelial immune complexes, usually accompanied by increased production of basement membrane-like material; accompanied by severe proteinuria or nephrotic syndrome; can occur concurrently with diffuse or focal lupus nephritis
What is advanced sclerosing lupus nephritis
Class VI: characterized by sclerosis of more than 90% of glomeruli; represents end stage renal disease
What do the skin changes in SLE show histologically
Vascular degeneration of the basal layer of the pidermis; in dermis, variable edema and perivascular inflammation
What SLE skin changes can you see on immunofluorescence
Deposition of immune complexes and complement along dermoepidermal junction in involved and uninvolved skin; not diagnostic of SLE (may also be seen in scleroderma and dermatomyositis))
What is different about the vegetations found in endocarditis in Libman Sacks versus infective endocarditis and rheumatic heart disease
Infective endocarditis the vegetations are larger; rheumatic heart disease are smaller
When is coronary artery disease seen in SLE patients
More common in young patients with noteable disease and especially prevalent in those who ha ve been treated with corticosteroids
What are common SLE affects seen in the spleen
Splenomegaly, capsular thickening, and follicular hyperplasia; central penicilliary arteries can show concentric intimacy and smooth m cell hyerplasia producing onion-skin lesions
What happens during acute flare ups of SLE
Increased formation of immune complexes and complement activation leads to hypocomplementemia; treated with corticosteroids or other immunosuppressants
What are the most common causes of death in SLE patients
Renal failure and inter current infections
What is chronic discoid LE
Skin manifestations mimic SLE, but systemic manifestations are rare; characterized by skin plaques showing edema, erythema, scaliness, follicular plugging, and skin atrophy surrounded by an elevated border; usually affects face and scalp; ANAs involved but rarely have abs to dsDNA; immunofluorescence shoes depositin of Ig and C3 at the dermoepidermal junction, similar to SLE
What is subacute cutaneous LE
Skin involvement, distinguished from discoid by: widespread, superficial, nonscarring; mild systemic symptoms consistent with SLE; association with abs to SS-A antigen and with HLA-DR3 genotype
What kind of treatment induces drug induced LE
Anti-TNF treatment (used to treat RA)
Do people with drug induced LE normally have symptoms
No, but tests positive for ANAs; those that do manifest symptoms such as fever, arthralgias, and serositis; renal and CNS involvement is highly uncommon
What abs are commonly seen in drug induced LE
Abs to histones; dsDNA is rare
People with what allele are at greater risk for developing LE-like syndrome after administration of hydralazine
HLA-DR4
People with what allele are at greater risk for developing LE-like syndrome after administration of procainamide
HLA-DR6
What is sjogren syndrome
Characterized by dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia) resulting from immunologically mediated destruction of lacrimal and salivary glands; can occur in primary form (isolated disorder) or in association with another autoimmune dz (secondary form) *RA most common associated disorder
