Immunology

1. Cells

   Annotations:

   • Hematopoetic Stem Cells
2. Innate Immune Response
   1. First line of defense
      1. Skin

         Annotations:

         • Acidic pH (5.6) maintained by subaceous glands inhibits microbial growth Skin produces psoriasins, small protein with antibacterial properties (especially effective against gram-negative species)  
         1. pH 5.6
         2. psoriasin
      2. Mucous

         Annotations:

         • Blocks the adherence of bacteria
         1. Blocks adherence
         2. surfactants

            Annotations:

            • Lowers surface tension, helps to clear bacteria
      3. Saliva
         1. Lysozyme

            Annotations:

            • especially effective against gram + species
      4. Urine
      5. Cilia
      6. Tears
         1. Lysozyme

            Annotations:

            • especially effective against gram + species
      7. Stomach
         1. gastric acid
   2. Non-specific
   3. No memory
   4. Fast
   5. Myelid ProgenitorCells
      1. RBC's
      2. Platelets
      3. Granulocytes
         1. Basophils
            1. Cytoplasmic Granules
               1. Prostoglandins

                  Annotations:

                  • increase bloodflow to infection site  -physiologically active lipids with hormone-like function 
               2. Heprin

                  Annotations:

                  • Anti-coagulant
               3. Histamine

                  Annotations:

                  • Smooth muscle contraction, vasodilation, increased capillary permeability 
            2. Nucleus often obscured by densely stained blue-purple granules
         2. Neutrophils

            Annotations:

            • A.K.A Polymorphonuclear neutrophilic (PMN) leukocyte
            1. 50-75% of total peripheral WBCs
            2. Nucleus Contains 2-5 segments
            3. Two types of Granules
               1. Specific Granules
                  1. Secondary Granules
                  2. Stain Neutral w/ Wright stain
                  3. 2/3 of all granules
                  4. Lysozyme

                     Annotations:

                     • Dismantles bacterial cell wall
                  5. Lactoferrin

                     Annotations:

                     • Takes iron from bacteria
                  6. Collagenase

                     Annotations:

                     • Breaks down collagen
                  7. Gelatinase

                     Annotations:

                     • Hydrolyzes gelatin
                  8. Respiratory burst componens

                     Annotations:

                     • Function in the oxidative burst that occurs during phagocytosis
               2. Azurophilic Granules
                  1. Primary Granules
                  2. 1/3 of all granules
                  3. Myeloperoxidase
                  4. Lysozyme

                     Annotations:

                     • Dismantles bacterial cell wall
                  5. elastase
                  6. Proteinase-3
                  7. Cathepsin G
                  8. Defensins

                     Annotations:

                     • Small Proteins with antimicrobial activity
            4. Moves from circulation to tissue via diapedesis
            5. Phagocytosis
            6. Attracted by Chemotaxins

               Annotations:

               • Chemotaxins are chemical messengers that cause cells to migrate in a particular direction
         3. Eosinophils
            1. 1-3% of circulating WBCs
            2. #'s increase during parasitic infection and allergies

               Annotations:

               • Use cationic proteins to damage cell membranes and kill parasites
            3. Bi-lobed nucleus
            4. Neutralizes basophil and mast cell products
            5. Function in regulation of immune system
            6. Stain with acid eosin dye
            7. Granules
               1. Cytokines
                  1. TGF β

                     Annotations:

                     • Tumor Growth Factor Beta
                  2. TNF α

                     Annotations:

                     • Tumor Necrosis Factor Alpha
                  3. IL-1

                     Annotations:

                     • Interleukin 1
                  4. IL-6

                     Annotations:

                     • Interleukin 6
               2. Catalase
               3. Lysozyme

                  Annotations:

                  • Dismantle bacterial cell wall
               4. Peroxidase
         4. Mast Cells

            Annotations:

            • Similar functions and appearance to Basophils. Made in the bone marrow
            1. Granules
               1. Histamine

                  Annotations:

                  • Smooth muscle contraction, vasodilation, increased capillary permeability 
               2. Acid phoshatase
               3. Alkaline phosphatase
               4. Protease
            2. Larger than Basophil
            3. Small Round Nucleus
            4. Found in skin, connective tissue, mucosal epithelial tissue of the respiratory tract etc.
            5. Role in allergic reactions
            6. Can act as APC
            7. Can enhance and suppress adaptive immune response
      4. Agranulocytes
         1. Monocytes

            Annotations:

            • 4-10% of circulating WBCs but don't stay in circulation long (about 30 hours) they migrate into tissues and become macrophages
            1. Macrophages
               1. Larger than Monocytes
               2. Loose peroxidase
               3. Name changes depending on the tissue they end up in (seems to be random)
               4. Activated by contact with microorganisms or by cytokines
               5. Regulates innate and adaptive immune response
               6. Function= Microbial killing, anti-turmor activity and eradication of intracellular parasites
               7. Phagocytotic and releases cell mediators
               8. APC: Presents antigenic peptides to CD4 + T helper cell
            2. Dendritic Cells
               1. Long membrane extentions make them look like nerve cells
               2. Classified by what tissue they are found in
               3. Most effective APC
                  1. Presents antigenic peptides to CD4+ T helper cell
               4. Most phagocytotic
               5. Found in lymphoid and non-lymphoid tissues
            3. Largest cell in peripheral blood
            4. Horse-shoe shaped nucleaus
            5. Migrate to tissues and differentiant into macrophages or dendritic cells
            6. Ground glass appearance from fine granules
   6. 1-4 hours
3. Adaptive Immune Response
   1. Slow
   2. Memory
   3. Specific
   4. Lymphoid Progenitor Cells

      Annotations:

      • Differentiates into Bcells Tcells or NK cells depending on exposure to cytokines
      1. Natural Killer Cells

         Annotations:

         • Comes from the Lymphoid line but seems to be non-specific
         1. CD56+ and CD16+

            Annotations:

            • Because of CD16 receptors NK cells can make contact with and lyse cells coated with antibodies
         2. Non specific and specific
         3. First line of defense against virally infected cells and tumor cells
         4. can develop memory
      2. T-Cells
         1. Made in the bone marrow
         2. Mature in Thymus

            Annotations:

            • T cells also called thymocytes
         3. Th- T helper cell

            Annotations:

            • Ratio of CD4+ to CD8+ in peripheral blood is 2:1
            1. CD4+
            2. Activates killer T cells and B cells
         4. Tc- Cytotoxic T cell

            Annotations:

            • Ratio of CD4+ to CD8+ in peripheral blood is 2:1
            1. CD8+
         5. Memory Cell
         6. Express diverse cell surface receptors (CD) cluster of differentiation
            1. recognize MHC molecules
            2. CD3 found on all Tcells
         7. Stimulate B-cells to produce antibodies
         8. Naive until it encounters antigen

            Annotations:

            • Then it becomes a mature Tcell and differentiated into an effector Tcell Those cells undergo clonal expansion and Differentiation into Th1, Th2, or Treg cell lineages is influenced by the spectrum of cytokines expressed in the initial response
         9. Tref- Regulatory Tcells

            Annotations:

            • Producing anti-inflammatory cytokines that suppress the immune response Releasing molecules that kill activated immune cells Changing the way dendritic cells behave so they can't activate T cells
            1. CD4+
            2. Shut off immune responses
            3. Suppress immune functions to prevent damage
      3. B-Cells
         1. Made and mature in the bone marrow
         2. Plasma Cell
            1. effector cell
            2. releases soluble antibodies
            3. Dont have a nucleus

               Annotations:

               • More space and cannot replicate
         3. Memory B cell
         4. Differentiate into plasma cells when activated
         5. Expresses surface antibodies
            1. IgM and IgD
         6. expresses MHC II
         7. CD19+ and CD21+
   5. 5-10 days

1. Primary Organs
   1. Bone Marrow
      1. Largest tissue in the body
      2. Main source of hematopoietic cells
      3. fills core of all flat bones
   2. Thymus
      1. Small, flat bilobed organ found in thorax
      2. Below thyroid
2. Secondary Organs
   1. Lymph nodes
   2. MALT

      Annotations:

      • Mucousal Associated Lymphoid Tissue
   3. CALT

      Annotations:

      • Conjunctiva Associated Lymphoid Tissue
   4. Spleen

1. Ligand-receptor interactions
   1. Pathogen surface markers (PAMPs)

      Annotations:

      • Pathogen associated molecular patterns
      1. peptidoglycan

         Annotations:

         • Gram+
      2. lipoproteins

         Annotations:

         • Gram-
      3. Zymosan

         Annotations:

         • yeast
      4. flagellin

         Annotations:

         • bacteria with flagellae
      5. Teichoic acid

         Annotations:

         • gram+
   2. Phagocyte surface receptors
      1. Pathogen recognition receptors (PRRs)
         1. neutrophils, eosinophils, macrophages, mast cells, t-cells and epithelial cells
         2. Bind to pathogens
      2. Toll-like receptors (TLRs)
         1. found on leukocytes and some other cell types
            1. Some on surface and some in cytoplasm
         2. Highest concentration on neutrophils, monocytes and macrophages
         3. Atleast 10 different TLRs

            Annotations:

            • TLR4- recognizes LPS TLR2- recognizes peptidoglycan and teichoic acid  TLR5- recognizes flagellin 
            1. Each receptor recognizes different microbial products
         4. TL4 binds LPS and SAA

            Annotations:

            • LPS- lipopolysaccharide SAA- Serum Amyloid A
         5. TLR2 bines to SAA
      3. C-type lectin receptors (CLR)
         1. monocytes, macrophages, dendritic cells, neutrophils, Bcells and some Tcells
         2. Bind to mannan and β-glucans on fungal cell walls
         3. Same end result and TLRs
   3. Lipopolysaccharide (LPS)
   4. Ligands
   5. Other Receptors
      1. RLR

         Annotations:

         • Retinoic acid-inducible gene-I-like receptors recognizes RNA from RNA viruses
      2. NOD

         Annotations:

         • nucleotide-binding oligomerization domain receptors bind peptidoglycan and protect against protozoan parasites
      3. Type 1 interferons

         Annotations:

         • inhibit viral replication induces apoptosis

1. Normal serum constituents
2. increase due to infection, injury ot trauma
3. produced by hepatocytes in response to cytokines
4. C -reactive protien
5. Serum amyloid A
   1. Binds to TLR2 and TLR4
6. Fibrinogen
7. Complement components
8. IL-1, IL-6, TNF-α
   1. Produced by monocytes and macrophages
9. Haptoglobin, ceruloplasmin, alpha1-antitrypsin

Annotations:

• Cytokines that function as part of the innate immune response by many different types of cells. Increases acute phase reactants. Recruits WBCs to affected area Cytokines that function as part of the adaptive immune response are secreted by mostly T-helper cells and affect the function of T and B cells.

1. Grouped into families
2. Functions:
   1. Pleiotrophy

      Annotations:

      • a single cytokine can have many different actions
   2. redundancy
   3. synergy
   4. antagonism
   5. cascade induction

      Annotations:

      • Cytokines released by a cell can activate the target and cause it to secrete additional cytokines e hyperstimulation of the immune response or hypercytokinemia (=cytokine storm)   Cytokine storms may lead to shock, multiorgan failure, or even death  
3. Tumor Necrosis Factor (TNF)
   1. Names because it induces lysis in tumor cells
   2. Membrane bound and soluble forms
   3. Increases vasodilation and vasopermeability
   4. TNF-α
      1. Mainly triggered by LPS
      2. secretes by activated monocytes and macrophages
      3. Activates t-cells by inducing the expression of MCHII
      4. When released at high levels can cause septic shock

         Annotations:

         • This condition results from large amounts of TNF secreted in response to gram-negative bacterial infections, causing • a decrease in BP • reduced tissue perfusion • disseminated intravascular coagulation, which may lead to uncontrolled bleeding
4. Transforming Growth Factor (TGF)
   1. TGF-β
      1. Differentiates Naive T-cells into Treg cells

         Annotations:

         • Treg reulates Th1 and Th2
5. Interleukins (IL)
   1. IL-1

      Annotations:

      • induces the production of vascular cell-adhesion molecules as well as chemokines and IL-6. These chemokines and cell-adhesion molecules attract and assist leukocytes to enter the inflamed area through a process known as diapedesis, which is the passage of leukocytes through the walls of the blood vessels into the tissues
      1. endogenous pyrogen

         Annotations:

         • Induces fever
         1. acts on the hypothalamus
      2. Both IL-1α and β are pro-inflammatory
      3. IL-RA
         1. Receptor antaonist
         2. blocks IL-1 signal
         3. Produced by monocytes and macrophages
      4. Triggers IL-6 secretion
   2. IL-6
      1. Stimulated proliferation and differentiation of B-cells

         Annotations:

         • B-cells differentiate into plasma cells
      2. induces cd4+ cells to produce pron-inflammatory cytokines
   3. IL-12
      1. drives Th1 cells
      2. cell mediated immunity
   4. IL-4
      1. regulates development of Th2
      2. antibody mediated immunity
      3. induces production of MCHI
      4. induces production of IL-4, IL-5 and IL-13
      5. induces production of CD80 and CD86
   5. IL-2
      1. drives growth and differentiation of B and T cells
      2. induces lytic activity of NK cells
   6. IL-10
      1. Primarily inhibitory affects
      2. anti-inflammatory and supressive affects on Th1
      3. Antagonist to IFN-γ
   7. IL-35
      1. promotes Treg growth
      2. Supresses Th1, Th2 and Th17 cells
6. Chemokines
   1. Primarily functions as a chemoattractant
      1. attracts migrating cells
7. Interferons (IFN)
   1. IFN-γ
      1. produced by Th1 cells
      2. affects the RNA expression of >200 genes
      3. stimulates antigen presentation of MHCI and MHCII
      4. potent activator of macrophages
         1. boosts tumoricidal activity
8. Colony Stimulating Factor (CSF)
9. Pro-Inflammatory
   1. IL-1
   2. IL-6
   3. TNF-α
   4. IFN-γ
   5. Sequence= TNF-α- > IL-1β -> IL-6
10. Anti-inflammatory
    1. TGF-β
    2. IL-10
    3. IL-13
    4. IL-35
11. Cytokine Storm

    Annotations:

    • In extreme circumstances, massive overproduction and dysregulation of cytokines produce hyperstimulation of the immune response or hypercytokinemia (=cytokine storm)