Cutaneous Immunology Flashcards
What are the two main “branches” of innate immunity?
Cellular vs non-celullar
What cells make up cellular innate immunity?
Macrophages, neutrophils, NK cells, mast cells, eosinophils, lymphocytes (especially cytotoxic T-cells)
What are some important components of non-cellular innate immunity?
Antimicrobial peptides - cathelicidins and defensins
Cytokines (IL-1, IL-10, IL-12, IFNa, IFNb)
Complement
TLR
What are the 3 primary complement pathways?
Classical, alternative, and mannose-binding lectin pathways
What is the difference between classical complement and alternative/mannose-binding lectin pathway activation?
Classical requires antibodies (It is activated by Antigen-Ab complexes [IgM or IgG])
Which IgG does not activate complement?
IgG4
In what order (strength) do IgG’s activate complement?
IgG3>IgG1>IgG2
What are the purposes of the complement cascade?
- opsonization, C3b>>C5b
- Lyse pathogen (membrane attack complex)
- increase chemotaxis (c3a, c5a) known as anaphalaxins.
What is the alternative pathway activated by?
Viral or bacterial products
What is the mannose-binding lectin pathway activated by?
Microbial carbohydrates like mannose and other monosaccharides on the bacterial wall
What cells are Toll-like receptors mostly expressed on?
Dendritic cells and macrophages
What pathway does activation of TLR activate?
NF-kB (Nuclear factor kappa beta)
Which TLR does NOT use MyD88 for intracellular signaling?
TLR3
Which TLR is activated by triacylated lipoproteins?
TLR1/TLR2
Which TLR is activated by diacylated lipoproteins?
TLR2/TLR6
Which TLR is activated by flagellin?
TLR5
Which TLR is activated by imidazoquinolines (imiquimod) and ssRNA?
TLR7/TLR8
Which TLR is activated by CpG DNA?
TLR9
Which TLR is activated by dsRNA?
TLR3
Which TLR is activated by LPS?
TLR4
Which TLR is affected by retinoids?
TLR2
Which TLR is involved in inflammatory acne?
TLR2 (As expected, this TLR is also affected by retinoids)
Which dermatologic medication affects TLR7?
Imiquimod (synthetic TLR7 analog)
Which complement fragment is the most potent anaphylatoxin?
C5a
Which complement fragments are anaphylatoxins?
C3a/C5a
List some important innate antimicrobial peptides that are important in dermatology and what secretes them
Human beta-defensin 1 (hbd-1) (keratinocytes)
- Human beta-defensin 2 (hBD-2) inducible by bacteria or cytokines
- Cathelicidin (LL-37) secreted by keratinocytes and granulocytes, upregulated in rosacea
- Psoriasin- inducible by bacteria or cytokines
Which defensins are affected in AD? And how?
cathelicidin (LL-37) and hBD-2 (human beta defensin2) are decreased in AD. (increased risk of infection)
Which innate immune defensins are affected in psoriasis?
Cathelicidin (LL-37) and hBD-2 (human beta defensin2) are increased in psoriasis (Thought to play a role in the decreased number of infections seen as compared to atopic dermatitis)
What cells produce the most cytokines?
T-cells
What is the main neutrophil chemoattractant/cytokine?
IL-8
True/False, do neutrophils express receptors for a complement?
Yes, they express receptors the Fc receptor for IgG and complement
In general terms, what do NK cells do?
Recognize antigen via opsonization (ab-dependant) or killer-activating /inactivating receptors.
How does MHC-1 expression change to activate NK cells?
Increased surface MHC-1 expression leads to cell death via granzymes (apoptosis), perforins (pores in cell membranes) and FAS and TRAIL ligand pathways
What are the primary immunohistologic markers for Langerhans cells?
CD1a, S100, vimentin, langerin
What is the main cytokine that modulates eosinophils?
IL-5 (Th2-cytokine)
What cells in the skin produce IL-1?
Monocytes, macrophages, and keratinocytes
What does IL-1 do?
Is proinflammatory –> induces fever, increases the production of acute-phase reactants, and increases expression of vascular endothelial cell adhesion molecules
Which interleukins are pro-inflammatory?
IL-1, IL-4, IL-6, TNFa
Which interleukins are “anti-inflammatory”?
IL-10, TGF-beta
What does IL-2 do and what cell produces it?
Activated T cells produce it –> Increased growth and activation of T, NK, and B cells
What does IL-3 do and what cell produces it?
T cells and stimulated myeloid cells –> Promotes growth of mast cells and enhances basophil production
What does IL-4 do and what cells produce it?
Th2 T helper cells –> Increases Th2 response, induces B cell class switching to increase IgE and increase MHC II production
What does IL-5 do and what cell produces it?
TH2 T-cells and mast cells –> stimulates eosinophils and stimulates B cells + Ig production (increases IgA too)
What does IL-6 do and what cell produces it?
Lymphoid cells and endothelial cells –> leads to the production of acute-phase proteins, stimulates B cells to differentiate to plasma cells and increases antibody secretion, and increases neutrophil production
What does IL-8 do and what cell produces it?
Keratinocytes and endothelial cells –> Neutrophil chemotaxis, member of the CXC chemokine family
What does IL-10 do and what cell produces it?
Th2 T-cells and keratinocytes –> Anti-inflammatory cytokine, inhibits pro-inflammatory cytokines along with inhibition of macrophages/dendritic cells; activates B cells, downregulates TH1 response
What does IL-12 do and what cells produce it?
Mononuclear phagocytes, dendritic cells –> Proinflammatory cytokine. It induces cell-mediated immunity like NK cells. Increases synthesis of IFNgamma and TNFa
What does IL-15 do and what cells produce it?
Mononuclear phagocytes –> Proliferative cytokine, increases NK cell proliferation, plus/minus T-cell growth factor
What does IL-18 do and which cells produce it?
Activated T-cells –> Proinflammatory, IFN-gamma inducing factor
What does TNF-alpha do and what cells produce it?
T-cells, mononuclear/phagocytes, mast cells, keratinocytes –> Proinflammatory, releases other proinflammatory cytokines like IL-1, IL-6 increases MHC I/II, activates T/B cells, induces fever and catabolism (cachexia)
What does IFNa/IFNb do and what cells produce it?
Leukocytes, fibroblasts –> Antiproliferative, antiviral, anti-oncogenic. Increase in I/II MHC expression, activates NK cells, has antifibrotic properties, and inhibits angiogenesis
What does IFN-gamma do and what cells produce it?
T-cells, NK cells –> Increased TH1 response –> primes macrophages, causes B-cell type switching to produce Ab
What does TGF-beta do and what cells produce it?
Activated platelets, keratinocytes –> Antiinflammatory, induces apoptosis, inhibits the growth of many cell lines/types, counteracts proinflammatory cytokines
What drugs trigger mast cell degranulation?
NSAIDs, opiates, asprin, vancomycin, polymyxin B, curare
What non-drug things can trigger mast cell degranulation?
Specific antigens (bridging of FceRI), anti-FceRI autoantibodies, IL-3, stem cell factor, C3a, C4a, C5a, radiocontrast media, and some neuropeptides
What two main branches make up the adaptive immune response?
Humoral (Antibodies) and cellular (T/B cells)
What two major/basic classes of T-cells exist?
CD4+ T-helper cells and CD8+ cytotoxic T-cells
What are the two major classes of CD4+ T-cells
TH1: Increases cell-mediated immunity, involved in delayed hypersensitivity reactions (type IV), and activates macrophages
TH2: Increases humoral mediated immunity through IL-4 and IL-5, switching to IgG4a and IgE, suppress macrophage activity.
Other important classes include T-reg, Th17, and other subtypes
Which cytokines favor the Th1 axis?
IL-2, IL-12, IFN-gamma, and TNF-a (High-Yield!)
Which cytokine(s) downregulate the Th2 axis?
IFN-gamma
Which cytokine(s) favor the Th2 axis?
IL-4, 5,6,and 10 (High-Yield)
Which cytokine downregulates the Th1 axis?
IL-10
What diseases are associated with Th1 dysfunction?
Allergic contact dermatitis, tuberculoid leprosy, leishmaniasis, psoriasis
What diseases are associated with Th2 dysfunction?
AD, lepromatous leprosy, dessminated leishmaniasis, sezarry syndrome, parasityci infection
What important cytokine in psoriasis favors the Th17 pathway?
IL-23
What drugs act on the IL-12/23 pathway in psoriasis?
Ustekinumab (Stelara) (also used in inflammatory bowel disease)
What cells express MHC-1?
All nucleated cells
What cell(s) recognize MHC-1?
CD8+ T-cells, NK cells
Where are antigens for MHC-1 processed?
In the cytosol
Qhat HLA types are associated with MHC-1?
HLA A/B/C
Which HLA MHC I subtype is associated with psoriasis?
HLA-Cw6
Which HLA MHC I subtype is associated with psoriatic arthritis and reactive arthritis?
HLA B-27
Which HLA MHC I subtype is associated with Behcets?
HLA-B51
What cells express MHC-II?
Antigen-presenting cells
Where do antigens get processed for MHC-II?
Endocytic vesicles
What cells recognize/respond to antigens on MHC II receptors?
CD4+ T-cells –> Promote a TH2 patheway–>more B cell activation –> antibody
*Dz’s with autoantibody follow this general pathway
What HLA subtypes are involved with MHC-II?
HLA DP/DQ/DR
Which HLA subtype is a/w lichen planus?
HLA-DR1
Which HLA subtype is a/w pemphigus vulgaris?
HLA-DR4
Which HLA subtype is a/w chronic urticaria?
HLA-DR4
Which HLA subtype is a/w dermatitis herpetiformis?
HLA-DQ2
What are the receptors and co-receptors that act as costimulatory molecules that are only found on T-cells?
CD 80 (B7-1) and CD86 (B7-2) which are co-receptors with CD28, and CD152 (CTLA-4) [both]
What receptor and co-receptor costimulatory molecules are ligands on T- and B-cells?
CD274 (PD-L1, B7H1) and CD273 (PD-L2, B7DC) and co-recpetor molecules CD279 (PD-1)
What are the main neutralizing antibodies?
IgA1/IgA2 (mucosal); IgG2/IgG4 (tissue)
What are the preformed mast cell mediators?
Tryptase, histamine, serotonin, and heparin
What factors are newly formed mast cell mediators (not pre-formed)?
Prostaglandin D2, Leukotriene C4, and Platelet-activating factor
What antibody class can cross the placenta?
IgG
Most abundant antibody class found in the circulation?
IgG
What complement pathways can IgA activate?
IgA can agglutinate with antigens and activate the alternate but not the classic pathway
What interleukins do keratinocytes produce?
IL-1, IL-6, IL-8, IL-10, IL-12, and TNF-alpha
What interleukins do keratinocytes respond to?
IL-2, IL-4, IL-13, IL-22, and TNF-alpha
What are the principal effects of IL-1 alpha/beta
Increase production of acute-phase proteins, fever, lymphocyte activation, macrophage activation, increased leukocyte/endothelial adhesion; involved in the innate immune inflammatory response
What is the function of IL-2?
The proliferation of T, B and NK cells. T-cell differentiation into different subsets including memory t-cells
What is the primary purpose of IL-4?
Isotype switching to IgE upon stimulation of B-cells. This increases Th2 cellular proliferation and differentiation
What is the primary purpose of IL-5?
Eosinophil activator, b-cell activation, increased IgA
What is the primary function of IL-6?
Involved in innate immune response and neutrophil production, b-cell differentiation and induction of acute-phase reactants
What is the main function of IL-8?
Chemokine –> Increases neutrophil chemotaxis
What are the main functions of IL-10?
Inhibition of macrophages/dendritic cells and proinflammatory cytokine production. Decreased expression of IL-12/Th1 response
What is the primary function of IL-12?
Activator of the Th1 response, increased interferon-gamma/TNF-alpha, enhances the cytotoxic activity of T and NK cells (cell-mediated immunity)
Has both a p40 and p35 subunit, which is important because IL-23 also has the p40 subunit
What is the primary function of IL-17?
Increases cytokine and chemokine production by keratinocytes and macrophages
this one is a key pathways in psoriasis
What is the main effect of IL-22?
Activation and proliferation of B-cells; proliferation of Th17 cells; stimulation of NK cells
What is the primary effect of IL-23?
Promotes Th17 proliferation and differentiation
Also has the p40 subunit like IL-12 (This is why ustekinumab interacts w/ IL-12 and IL-23)
this one has a key role in psoriasis
What is the main effect of TNF-alpha?
Activation of macrophages and T and B lymphocytes, increased proinflammatory cytokine production, leukocyte/endothelial cell adhesion, cachexia, pyrexia, induction of acute-phase proteins and increased MHC class I induction
What is the main effect of interferon-alpha?
Activation of antiviral/antitumor state (antiproliferative), Increased MHC I expression, NK-cell activation
What is the main effect of interferon-beta?
Activation of antiviral/antitumor state (antiproliferative), Increased MHC I expression
What is the main effect of interferon-gamma?
MHC class I and II induction, macrophage activation and cytokine synthesis, increased endothelial cell/lymphocyte adhesion antiviral state, antiproliferative (Th1 cells), differentiation of the Th1 cells, isotype switching with opsonization activity, macrophage activation, increased MHC I/II expression; downregulation of Th2 pathway
What are the main cytokines released by macrophages?
IL-1a/b, IL-10, IL-12, IL-18, TNF-alpha, G-CSF, GM-CSF
What are the main cytokines released by T-cells?
Th2: IL-4, IL-5, IL-22
Th17: IL-17, IL-22
Treg: IL-10,
T-cells (general): IL-2, IL-3, IL-6, IL-8, IFN-gamma
What cytokines are released by monocytes?
IL-8, IL-15
What cytokines are released by B-cells?
IL-1a/b, IL-6, TNF-alpha (lymphocytes)
What component of complement binds antibodies?
C1q binds the Fc portion of the antigen-bound antibodies, the other components of the C1 3 protein complex are C1r and C1s. C1s cleaves C4 and then c2 to make the C3 convertase (C4b/c2a which then turns C3 to C3a and C3b
What complement components make up the MAC?
C5b, C6, C7, C8, and C9
What cell lineage are NK cells from?
They are lymphocytes
What are the primary B-cell immunohistochemical markers?
FC receptor, MHC class II, complement receptors, CD19, CD20, CD79a
What is required for a T-cell receptor to recognize an antigen?
TCR’s require the antigen to be teamed with an MHC I/II receptor and costimulatory signals
What are the main co-stimulatory receptors located on the T-cell and what do they interact with?
- CD28 on the T-cells binds with B7-1 and B7-2 on APC’s
- CD2 on T-cells binds to LFA-3 on APC’s
- LFA-1 on T-cells binds to ICAM-1 on APC’s
What are some co-inhibitory receptors on the T-cell and what do they interact with?
CTLA4 is on the T-cell and interacting with B7-1 and B7-2 and leads to inhibition.
What cytokine is released when T-cells are activated and what does it do?
IL-2 is released and it leads to the proliferation of antigen-specific T-cells
What are the main Immunohistochemical markers on T-cells?
CD2, CD3, CD4 (helper t-cells), CD8 (on cytotoxic t cells)
How are Th1 cells activated and what is their primary function?
Activated by intracellular pathogens, these activate macrophages, and then the Th1 response is mediated by macrophage activity
- the Th1 response is important for cell-mediated immunity and delayed-type hypersensitivity reactions
- Stimulate IgG2 and IgG3 class switching
- Promote phagocytic activity through INF-gamma mediated macrophage activation, FcgammaRIII crosslinking, complement deposition, opsonization
- Requires stimulation by IL-12 and INF-gamma (mediated through T-bet, STAT1, and STAT4 signaling)
- Th1 cells produce INF-gamma, IL-2, IL-12, and TNF-alpha
What is the function of the Th2 response, how is it triggered, what chemokines are produced as a result?
Th2 cells activate eosinophils which help mediate systemic immune responses against helminthic parasites and downregulate macrophage activity.
- Also important in humoral immunity
- IL-4 is the key cytokine that stimulates Th2 proliferation by activating STAT6 and GATA-3
- Th2 cells produce: IL-4, IL-5, IL-6, IL-10 (decreases Th1 response), IL-13 (important in allergies, acts like IL-4)
- Stimulates IgG4 to IgE
- Response mediated by mast cells and eosinophils
- Increases degranulation through FcepislonR1 cross-linking, IL-5 mediated eosinophil activation
What activates, what is the purpose of, and what things do Th17 activate?
Th17 requires activation of the transcription factors RORgammT, STAT3 (mutated in job’s syndrome), and TGF-beta
- The purpose of these cells is to recruit neutrophils to an area to destroy extracellular pathogens
- Produce IL-6, IL-17, IL-22 (increases keratinocytes), IL-23 (essential for survival/division of cells), IL-36, and TNF-alpha
- activate local endothelium, induce cytokine and chemokine production, increase neutrophils infiltration, activate cell-mediated inflammation
What is the purpose of Tregs and what factors are expressed on these?
Downregulate immune response, express CD25 and transcription factor FOXP3
How do CD8+ T-cells kill their target cells?
Via the perforin/granzyme pathway: perforin enables granzyme to enter the cytoplasm of virally infected cells leading to apoptosis.
-Also, Fas ligand on thse cells can bind Fas on target cells leading to cell death
What is the predominant type of TCR construct of t-cells (alpha/beta vs gamma/delta)?
alpha/beta is the most common
What is the purpose of gamma/delta T-cells?
They act like Treg’s, they suppress the immune system via IL-10 which is why they make such aggressive lymphomas (suppress immune detection and attack)
What are the cell surface markers for NK cells?
CD2, CD56, CD16
What cells do NK cells attack?
These attack cells which have decreased MHC-I on their surface (viral infected) and destroy via perforin/granzymes
What cytokines activate NK cells and what cytokines do they produce?
NK cells are activated by: IL-12, IL-15, and type I interferons
NK cells secrete INF-gamma and enhance the phagocytic capability of macrophages and have cytoplasmic granules that are similar to CD-8+ cytotoxic t-cells
What are the cellular markers for macrophages?
CD11a/b/c, CD6, Fc receptor for IgG, and MHC-II, come from CD34+ progenitor cells
What are the immunohistological markers for Mast cells?
CD34/c-kit (CD117)/CD13
What are the main neutrophil chemotactic factors?
C5a, IL-8, LTB4, Kallikrein
What chemokines are required for Langerhans cell development?
TGF-beta and macrophage colony-stimulating factor receptor (M-CSFR) ligant for development
What is the function of Langerhans cells
They are poor at phagocytosis but they are professional antigen-presenting cells. They take up antigens and then travel to the lymph nodes where the MHC-bound antigen is presented to T-lymphocytes followed by subsequent activation of T-lymphocytes
What do Langerhans cells stain + for?
S100+, langerin (CD207)+ (most sensitive and specific), vimentin +, and CD1a+
What is a major difference between the types of antigens that a B-cell will recognize and a t-cell will recognize?
T-cells require that the antigen be attached to an MHC molecule whereas the B-cells can pick up antigens. The response from this initial contact is not as robust and leads to IgM not the other Ig’s
What are key differences in the antigens presented by MHC-1 vs MHC-II?
MHC-1 molecules are intracytoplasmic (think virus/cancer), so they get transported to the ER and then put on the receptor and shipped out.
MHC-II are for extracellular antigens that APC’s pick up, so they are engulfed and then processed in the vehicles in the cytoplasm where the receptors are loaded and presented.
What components of the complement pathway are the main drivers of opsonization?
C3b>>C5b
