USMLE - Immune System Part 1
Innate immunity uses germline-encoded receptors to detect pathogens quickly and nonspecifically.
Innate Immunity
Receptor coding?
Response to pathogens is
Memory?
Cells involved?
Molecules involved?
Receptors that recognize pathogens are germline encoded
Response to pathogens is fast and nonspecific
No Memory
Neutrophils, Macs, Dendritic Cells, Natural Killer Cells (lymphoid origin)
Complement
Key Terms
Innate Immunity
Receptor coding?
Response to pathogens is
Memory?
Cells involved?
Molecules involved?
Receptors that recognize pathogens are germline encoded
Response to pathogens is fast and nonspecific
No Memory
Neutrophils, Macs...
Adaptive Immunity
Innate Immunity
Receptor coding?
Response to pathogens is
Memory?
Cells involved?
Molecules involved?
Receptors that recognize pathogens undergo V(D)J recombination during lymphocyte development
Response is slow on first exposure. Memory respo...
MHC
Stands for
Encoded by what gene?
Function
What does it bind?
Major Histocompatibility Complex
Human Leukocyte Antigen (HLA) gene
Presents antigen fragments to T cells and binds TCR
MHC I
Genes encoding it?
Binds what receptors
Which cells express it?
Where is antigen loaded
What kind of antigens?
What kind of immunity does it mediate?
What does it pair with and why?
Where is peptide groove?
HLA A, B and C
Binds TCR and CD8
All nucleated cells (not RBCs)
Antigen loaded in RER with mostly intracellular peptides
Me...
MHC II
Genes encoding it?
Binds what receptors
Which cells express it?
When is antigen loaded
What does it look like?
HLA DR, DP and DQ
Binds TCR and CD4
Expressed only on APCs
Antigen is loaded following release of invariant chain in an acidified...
Association with HLA A3
Hemochromatosis
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| Term | Definition |
|---|---|
Innate Immunity Receptor coding? Response to pathogens is Memory? Cells involved? Molecules involved? | Receptors that recognize pathogens are germline encoded Response to pathogens is fast and nonspecific No Memory Neutrophils, Macs, Dendritic Cells, Natural Killer Cells (lymphoid origin) Complement |
Adaptive Immunity Innate Immunity Receptor coding? Response to pathogens is Memory? Cells involved? Molecules involved? | Receptors that recognize pathogens undergo V(D)J recombination during lymphocyte development Response is slow on first exposure. Memory response is faster and more robust. T and B cells Antibodies |
MHC Stands for Encoded by what gene? Function What does it bind? | Major Histocompatibility Complex Human Leukocyte Antigen (HLA) gene Presents antigen fragments to T cells and binds TCR |
MHC I Genes encoding it? Binds what receptors Which cells express it? Where is antigen loaded What kind of antigens? What kind of immunity does it mediate? What does it pair with and why? Where is peptide groove? | HLA A, B and C Binds TCR and CD8 All nucleated cells (not RBCs) Antigen loaded in RER with mostly intracellular peptides Mediates viral immunity Pairs with β2 microglobins (aids in transport to cell surface) Peptide groove in α chain |
MHC II Genes encoding it? Binds what receptors Which cells express it? When is antigen loaded What does it look like? | HLA DR, DP and DQ Binds TCR and CD4 Expressed only on APCs Antigen is loaded following release of invariant chain in an acidified endosome α and β chains pair with peptide groove in between |
Association with HLA A3 | Hemochromatosis |
Association with HLA B27 | “PAIR” Psoriasis, Ankylosing Spondylitis, IBDm Reiter’s syndrome |
Association with HLA DQ2/DQ8 | Celiac |
Association with HLA DR2 | Multiple Sclerosis, Hay Fever, SLE, Goodpastures |
Association with HLA DR3 | DM type 1, Graves’ Disease |
Association with HLA DR4 | RA, DM type 1 |
Association with HLA DR5 | Pernicious anemia (B12 deficiency), Hashimoto’s thyroiditis |
Natural Killer Cells What do they do? What do they use to do it? How are they unique? What molecules enhance their activity? When are they induced to kill? | Induce apoptosis in virally infected cells or tumor cells Use perforin and granzymes Only lymphocyte member of innate immune system “#2, get #12, tell him the boss needs to take out α and β” Activity is enhanced by IL2, IL12, INFα, INFβ Induced to kill when exposed to a nonspecific activation signal on target cell +/or to an absence of MHCI on target cell surface |
B cells functions | Make Abs: opsonize bacteria, neutralize viruses (IgG), Activate complement (IgM and IgG), Sensitize mast cells (IgE) Allergy (Type I hypersensitivity): IgE Cytotoxic (Type II hypersensitivity): IgG Immune Complex (Type III hypersensitivity): IgG Hyperacute and humorally mediated acute and chronic organ rejection |
T cell functions Generally CD4 CD8 | Delayed cell mediated hypersensitivity reaction (IV) Acute and chronic cellular organ rejection CD4+ cells help B cells make Ab and produce cytokines to activate other cells of the immune system CD8+ cells kill virus infected cells directly |
Differentiation of T cells In Bone Marrow In Thymus In Lymph Node | In BM: T cell precursor In T: expresses TCR, CD4 and CD8 and then will switch to only expressing one of the CDs and a TCR In LN: CD8+ --> cytotoxic T cells CD4+: if exposed to IL12 --> Th1 if exposed to IL4 --> Th2 |
Where is there Positive selection in T cell differentiation? | In the Thymic Cortex where T cells expressing TCR capable of binding self MHC survive |
Where is there Negative selection in T cell differentiation? | Medulla where T cells expressing TCR with high affinity for self antigens undergo apoptosis |
APCs # of signals needed for what? | Dendritic cell (Only APC that can activate naive T cell) Macrophage B cel |
Steps of naive T cell activation | Foreign body is phagocytosed by dendritic cell Foreign antigen presented on MHCII MHCII + antigen recognized by TCR on Th cell or MHCI + antigen recognized by TCR on Tc cell Costimulatory signal given by interaction of B7 (DC) and CD28 (T cell) T cell activated: Th produced cytokines, Tc kills virus infected cells |
Steps of B cell activation and class switching | Th cell activated B cell receptor mediated endocytosis Foreign antigen presented on MHCII MHCII + antigen recognized by TCR on Th cell CD40 receptor on B cell binds CD40 ligand on Th cell Th cell secretes cytokines that determine Ig class switching of B cell B cell activates and undergoes class switching, affinity maturation, and Ab production |
Th1 What do they secrete What do they activate What inhibits them | Secretes INFγ Activates Macs Inhibited by IL4 and IL10 from Th2 |
Macrophage-Lymphocyte interaction | Activated lymphocyte –> INFγ –> Macs –> IL1 and TNFα –> lymphocytes |
Th2 What do they secrete What do they activate What inhibits them | Secrete IL4, IL5, IL10, IL13 Recruit eosinophils for parasite defense, promote IgE production by B cells Inhibited by INFγ from Th1 |
Lymph Node What is it? Afferents? Efferents? Encapsulated? Function | Secondary Lymphoid Organ Many afferent Encapsulated w/ trabeculae Filtration by Macs, storage, activation of B and T cells, Ab production |
Lymph Node Follicle Location Function Primary vs Secondary | Outer cortex B cell localization and proliferation Primary: dense and dormant Secondary: pale central germinal centers and are active |
Lymph Node Medulla | What does it consist of? | Medullary cords: closely packed lymphocytes and plasma cells Medullary sinuses: Communicate with efferent lymphatics and contain reticular cells and Macs |
Paracortex Location What does it house? What does it contain? What happens in an extreme cellular response? Disease? | Between follicles and medulla T cells High endothelial venules through which T and B cells enter from blood In extreme celular response, becomes enlarged Not well developed in DiGeorge Syndrome |
Lymph Drainage of Upper limb and lateral breast | Axillary |
Lymph Drainage of Stomach | Celiac |
Lymph Drainage of Duodenum and Jejunum | Superior Mesenteric |
Lymph Drainage of Sigmoid Colon | Colic --> Inferior Mesenteric |
Lymph Drainage of lower rectum and anal canal above pectinate line | Internal Iliac |
Lymph Drainage of Anal Canal Below Pectinate Line | Superficial Inguinal |
Lymph Drainage of Testes | Superficial and Deep Plexuses --> Para-Aortic |
Lymph Drainage of Scrotum | Superficial Inguinal |
Lymph Drainage of Thigh | Superficial Inguinal |
Lymph Drainage of Lateral Side of Dorsum of the foot | Popliteal |
What does Right Lymphatic Duct drain? | What does Thoracic Duct drain? | Right arm, right chest, Right half of head | Everything else |
Sinusoids of the Spleen What are they? What are found nearby | Long Vascular Channels in red pulp with fenestrated "barrel hoop" basement membrane Macrophages found nearby |
Where are T cells in the spleen? | Periarterial lymphatic sheath (PALS) w/in white pulp |
Where are B cells in the spleen? | Follicles w/in white pulp |
What do macrophages do in the spleen? | Remove encapsulated bacteria |
Splenic Dysfunction Pathway What are pts susceptible to? | ↓ IgM --> ↓ Complement activation --> ↓ C3b opsonization --> ↑ susceptibility to encapsulated organisms "SHiNE SKiS" Strep pneumoniae, Haemophilis influenza type B, Neisseria meningitidis, Salmonella, Klebsiella pneumoniae, Group B Strep, E coli |
Blood of pt post Splenectomy | Howell Jolly Bodies, Target Cells, Thrombocytosis |
Thymus Function Encapsulated Development Origin of lymphocytes | Site of T cell differentiation and maturation Encapsulated From epithelium of 3rd Branchial pouches Lymphocytes of mesenchymal origin |
Thymus Cortex Appearance Kind of T cells there? Kind of selection | Dense Immature T cells Positive selection (MHC restriction) |
Thymus Medulla Appearance Kind of T cells there? Histo Kind of selection | Pale Mature T cells Epithelial Reticular cells containing Hassall's Corpuscles Negative Selection (nonreactive to self) |
Cytotoxic T cells Function What doe they release Markers | Kill virus-infected cells, Neoplastic, and donor graft cells by inducing apoptosis Release cytotoxic granules containing preformed proteins (Perforin, Granzyme, Granulysin) CD8 |
Perforin Granzyme Granulysin | Perforin: Helps deliver the content of granules to target cells Granzyme: Serine Protease activates apoptosis inside target cells Granulysin: Antimicrobial, induces apoptosis |
Regulator T cells Function Markers What doe they produce? | Help maintain specific immune tolerance by suppressing CD4 and CD8 T cells CD3, CD4, CD25 (α-chain of IL2 receptor) IL10 and TGFβ |
What part of Ab recognizes Ag | Variable portion of L and H chains |
Function of Fc portion of IgM and IgG | Fix complement |
Composition of Fc and Fab fractions Re H and L chains | H contributes to both Fc and Fab | L contributes only to Fab |
Fab functions | Ag binding fragment |
Fc portion What is it? Which end of the protein? Function Side chains What does it determine? | Constant portion Carboxy terminal Complement binding @ CH2 (IgM and IgG only) Carbohydrate side chains Determine isotype (IgM, IgD...) |
How is Ab diversity generated? | Light chain undergoes random VJ recombination H undergoes random VDJ recombination Random combination of H and L chains Somatic Hypermutation following Ag stimulation (AID) Addition of NTs to DNA during recombination by Terminal Deoxynucleotidyl Transferase |
Mature B lymphocytes express what on their surface? | IgM and IgD |
What mediates Isotype switching | Cytokines and CD40 ligand |
IgG Main Ab of what? Abundance? Function | Secondary Delayed Response Most abundant type Fixes complement, Crosses Placenta, Opsonizes bacteria, Neutralizes bacterial toxins and viruses |
IgA Function Complement? Single or group? How does it cross epithelial cells Where is it found? | Prevents attachement of bacteria and viruses to mucous membrane Doesn't fix complement Monomer in circulation, Dimer when secreted Transcytosis where it picks up secretory component Secretions (tears, saliva, mucus) and early breast milk (colostrum ) |
IgM When is it produced? Function Placenta? Single or group? | Primary immediate response to Ag Fixes complement Does not cross placenta Monomer on B cells or Pentamer |
IgD Location Function | Surface of B cells and in serum | Unclear function |
IgE Mediates what kind of Immunity? Function Abundance | Mediates immediate (type I) hypersensitivity through release of inflammatory mediators (histamine). Mediates immunity to worms by activating eosinophils Binds mast cells and basophils. Cross links when exposed to allergen Lowest concentration |
Thymus Independent Antigens What is it? What do they stimulate Memory? | Ags lacking peptide component and thus cannot be presented on MHC to T cells Stimulate release of Ab Do not result in memory |
Thymus Dependent Antigens What is it? What do they stimulate Memory? | Ags containing protein component Stimulate class switching Memory results of direct contact of B cells w/ Th cells (CD40-CD40 Ligand interaction) |
C3b | Opsonization |
C3a and C5a | Anaphylaxis |
C5a | Neutrophil Chemotaxis |
C5b-9 | Cytolysis by MAC |
Complement Pathways | Classic: IgG and IgM Alternative: Microbe Surface Molecule Lectin: Mannose or other sugars on microbe surface |
Opsonins | IgG and C3b |
Inhibitors of Complement pathway | Decay-Accelerating Factor (DAF) and C1 esterase inhibitor |
Alternative Complement Pathway | Spontaneous and Microbal Surfaces turn C3 into C3b B --> [D] --> Bb C3 --> [C3bBb (C3 Convertase)] --> C3a + C3b |
Classic Complement Pathway | Ab --> C1 C2 --> [C1] --> C2a and C2b C4 --> [C1] --> C4a and C4b C3 --> [C4bC2a (C3 convertase)] --> C3a + C3b |
Lectin Complement Pathway | Mannose Binding Lectin --> [MASP] --> C1-like Complex C4 --> [C1LC] --> C4a + C4b C3 --> [C4b2a] --> C3a + C3b |
Common Complement Pathway | C3bBb3b (C5 convertase) C4b2a3b (C5 convertase) C5 --> [C5 convertase] --> C5a + C5b C5b + C6 through C9) = MAC |
C1 Esterase Inhibitor Deficiency Presentation Contraindications | Hereditary Angioedema | ACE inhibitors Contraindicated |
C3 Deficiency Presentation | Severe, recurrent pyogenic sinus and respiratory tract infections Susceptibility to Type III hypersensitivity reactions |
C5-C9 Deficiency | Recurrent Neisseria Bacteremia |
DAF (GPI anchored enzyme) deficiency | Complement mediated lysis of RBCs and Paroxysmal Nocturnal Hemoglobinuria |
IL1 Secreted by what cell? Function | Macrophages Endogenous pyrogen. Causes fever, acute inflammation, activates endothelium to express adhesion molecules, Induces chemokine secretion to recruit leukocytes |
IL6 Secreted by what cell? Function | Macrophages and TH2 | Endogenous pyrogen. Fever and Production of acute phase proteins |
IL8 Secreted by what cell? Function | Macrophages | Neutrophil chemotactic |
IL12 Secreted by what cell? Function | Macrophages and B cells Induces differentiation of Th1 cells Activate NK cells |
TNFα Secreted by what cell? What does it mediate? Function | Macrophages Mediates septic shock Activates endothelium, Leukocyte recruitment, Vascular leak |
Interleukin Mnemonic | "Hot T-Bone stEAk" IL1: Hot (fever) 2: stimulate T cells 3: Stimulates Bone marrow 4: IgE 5: IgA |
Cytokines secreted by all T cells w/ function | IL2: Stimulates growth of Th, Tc, and Treg cells IL3: Supports growth and differentiation of bone marrow stem cells (like GM CSF) |
Interferon-γ What kind of cells secrete it? Function | Th1 cells Activate Macrophages and Th1 cells Suppresses Th2 cells Antiviral and antitumor properties (upregulates MHCI and MHCII and Ag presentation in all cells) |
Cytokines secreted by Macrophages | 1, 6, 8, 12, TNFα |
Cytokines secreted by Th2 cells | 4, 5, 6, 10 |
IL4 What kind of cells secrete it? Function | Th2 Induces differentiation into Th2 cells Promotes growth of B cells Enhances class switching to IgE and IgG |
IL5 What kind of cells secrete it? Function | Th2 Promotes differentiation of B cells Enhances class switching to IgA Stimulates Eosinophils |
IL10 What kind of cells secrete it? Function Like what other molecule | Th2 and Treg Modulates immune response Inhibits actions of activated T cells and Th1 Similar to TGFβ in that it inhibits inflammation |
Interferon Kinds Function | α, β, γ Place uninfected cells in an antiviral state Induce production of ribonuclease that inhibits viral protein synthesis by degrading viral mRNA Activate NK cells |
IFNα and IFNβ function | Inhibit viral protein synthesis |
T cell surface markers Th Tc | T: TCR, CD3 (associated with TCR), CD28 (binds B7 on APC) Th: CD4, CD40 lingand Tc: CD8 |
B cell surface markers | "Drink Beer at the Bar when you're 21" | Ig, CD19, CD20, CD21 (EBV receptor), CD40, MHCII, B7 |
Macrophage surface markers | CD14, CD40, MHCII, B7, Fc receptor, C3b receptor |
NK cell surface markers | CD16 (binds Fc of IgG), CD56 |