4.1a Immunity

PATHOLOGY SPECIFIC NOTES - Why are you lazy? Read the whole thing you’re better off. Well, choice is an illusion

Immunity is divided into

  • Innante
    • Non-specific
    • No memory (amnesic)
  • Adaptive
    • specific
    • Memory (a-amnesic)

Innate Immunity

Innate immunity is the inborn resistance against infections that an individual possesses right from the birth, due to his genetic or constitutional makeup.

  • Barriers

    • Anatomical [skin]
    • Physiological [Secretions and their contents]
  • Proteins

    • C-reactive proteins
    • Lectin
      • e.g: Mannose Binding Lectins [CD14 of macrophage recognizes]
    • Complement proteins
    • Surfactants and plasma proteins
  • Cells

    • Neutrophils
    • Macrophages
    • NK Cells
      • Natural Killer (NK) Cells are lymphocytes in the same family as T and B cells, coming from a common progenitor. However, as cells of the innate immune system, NK cells are classified as group I Innate Lymphocytes (ILCs) and respond quickly to a wide variety of pathological challenges.
      • They kill virus infected cells
      • Kills tumor cells

How are pathogens recognized?

Pattern Recognition receptors

  • Bacteria:
    • Pathogen/Microbe Associated Molecular Patterns
  • Inflammation
    • Damage Associated Molecular Patterns

Types:

  • Toll-like receptor
    • Causes activation of
      • NF-NF-κB(Nuclear factor kappa-light-chain-enhancer of activated B cell - a transcription factor)
        • Causes recruitment of leukocytes
        • Activates COX-2
      • IFN-1 (type 1)
        • Antiviral action ]
  • C-type LR (Lectin Receptor)
    • Important against fungal infections

Cytosolic Receptors

  • RIG-like receptor
    • Act against viral nucleic acids
  • NOD-like receptor
    • Identifies:
      • Bacteria
      • K+ levels (eflux)
      • Uric Acid
      • ROS
    • Activates inflammasome
      • Which activates Caspase 1 -> IL1 -> Fever Inflammation

NK-Cells

This is a component of Innate Immunity

Hematopoitic Stem Cells -> Lymphoid Stem Cells

  • Lymphoid Stem Cells then differentiates
    • In Thymus gland: T cell
    • In Bone Marrow: B-Cell
    • Naive: Natural Killer Cells
      • Innate Lymphoid Cells

NK-Cells

  • They can secrete cytokines like T-cells
  • They do not have TCR
  • They were earlier known as Large Granular Lymphocytes [LGL]
  • They kill virus infected cells
  • Kills tumor cells

[[Pasted image 20210708230309.png]]

Two important receptors

  • Stimulatory/Activating receptor
  • Inhibitory Receptor
    • All cells in the body have MHC Class I molecule
    • This stimulates the inhibitory receptor
  • MHC class I has reduced expression in mutated cells (tumors) or viruses
  • Virus and cancer tumors have molecules that amplify molecules that activate the Activating receptor

NK cells also have

  • CD16
    • Also known as Fc receptor
    • Fc portion of the ImmunoglobulinG attaches to this
      • NK-cell destroys the coated antigenic cell
      • Antibody Dependent Cell Mediated Cytotoxicity [CDCC]
  • CD56

Adaptive Immunity

  • specific
  • Memory (a-amnesic)
  • Contributed by
    • T-cells - Cell-mediated
      • Effective against intracellular microbeszb
    • B-Cells - Humoral immunity
      • Effective against extracellular microbes

B-cells

  • Located in the

    • Lymph node
    • Spleen
    • GIT
      • Mucosa Associated Lymphoid Tissue MALT
        • Present highly in the Peyer’s patches of the Ileum
      • Enteric fever is due to the ulceration of Peyer Patches and thus commonly it’s in the ileum
    • Tonsils
  • The lymph node has muliple zones

    • Cortex - B Cells
    • Paracortex - T-cells
    • Medulla Macrophages

[[Pasted image 20210707215520.png]]

B-Cell markers

CD stands for Cluster of Differentiation

  • CD 19 to 23 (1923)
    • CD19 - Pan B Marker (present in all stages of B-cell development)
    • CD21 - Receptor for EBV (Epstein Barr Virus)
  • CD 40
    • CD40 ligand is expressed on the T-cells
      • CD40L of T-cell and CD40
      • B-cell : T-cell interaction
      • Important in production of high quality antibody formation
  • CD80 / B7-1 CD86 / B7-2
    • CD80/86 are known as the B7 (B7-1 and B7-2 respectively)
      • These interact with CD28 on the T-cell to produce co-stimulatory signal

B-cells on activation -> Plasma-cell

  • Plasma cells secrete antibodies (immunoglobulins)

Immunoglobulins

[[Pasted image 20210707220953.png]]

Made up of:

  • Light Chains
    • λ (lambda)
    • κ (kappa)
  • Normal ratio : 3:1 to 3:2 κ:λ
  • Heavy Chains
    • α (alpha)
    • γ (gamma)
    • δ (delta)
    • ε (epsilon)
    • μ (mu)
  • Isotype
    • Different classes of antibodies in the same person
  • Allotype
    • Difference in antibody taken from two people
  • Idiotype
    • Variable part of antibody is different in same person

Immunoglobulin Classes / Isotypes

  • These are dependent upon the heavy Chains present

IgG

  • Presence of Gamma γ heavy chain
    • Maxiumum concentration
    • Crosses Placenta
    • Complement Activation
    • Opsonization

IgA

  • Presence of the Alpha heavy chain
    • Forms:
      • Monomer in the Serum
      • Dimer in the Mucosa and Secretions - joined by J joining chain
  • First Line of Defense (as majority of the infections have to pass through mucosal layer)
    • It activates the Alternate pathway rarely

IgM

  • Presence of mu heavy chain
  • M for
    • Max Size
      • Pentameric
    • Max Molecular Weight
  • Complement Pathway Activation
    • Primary Immune Response - IgM is mostly produced than IgG (predominant)
  • Monomeric form is present on B-Cell Receptor

IgD

  • Presence of Delta Heavy Chain
  • Functions as acts as B-cell receptor

IgE

  • Presence of Epsilon Heavy Chain
  • Lowest Concentration
  • Attached to the surface of Mast Cells
    • Responsible for Type-1 Hypersensitivity Reaction
  • Heat labile antibody

Antigens

  • Exogenous
  • Endogenous
  • Autogenous
Types of Antigens based on B-Cell activation
Non-Proteinaceous
Proteinaceous/T-Cell Dependent

Non-Proteinaceous Antigens

  • These are free antigens that do not require any additional cells for activation
    • Thus also known as thymic-independent antigens/T-cell independent
    • Pentameric IgM antibodies are produced when bound to monomeric form of IgM present on BCR
  • Leads to T-cell indepent activation of B-Cell

[[Pasted image 20210707224227.png]]

Proteinaceous Antigens

  • Requires the support of T-CeLLS for proper activation of Immune System

[[Pasted image 20210707224246.png]]

  • B-Cell or APCs (antigen presenting cells) expresses antigen on the surface
  • T-CR (T-cell receptor) then recognizes the antigen
  • T-cell then attaches to the MHC class
  • CD40(B-cell) and CD40L (T-Cell) interaction occurs
    • This leads to secretion of IL-4/IL-5
    • Cytokine Reference
    • This causes IgM -> IgG/A/E [isotype/class switching : change in heavy chain by IL-4/IL-5]
      • This is reaaallyy important for somatic hypermutation ^4e39b6
      • If this is cytokine secretion is blocked -> Hyper IgM syndrome

T Cell

  • Named from the fact that they develop in the thymus
  • Present in the
    • Lymph Node

      • Paracortex

      [[Pasted image 20210707215520.png]]

    • Spleen

      • Periarteiloar Lymphoid Sheath
        • PALS
    • GIT

      • Present within the intraepithelial lymphocytes [IELs] | compare this with B cells in the mucosal lymph node (MALTS)

Structure

  • T-cell Receptor (TCR)
    • Binds to prebound antigens only
    • Prebound antigens are presented by APCs
  • CD molecules
    • CD 1 to 5, 7 and 8 [CD1 CD2 CD3 CD4 CD5 CD7 CD8]
      • These are all T-cell markers
      • Pan-T-Cell Marker - CD3
        • Significant in signal transduction mechanism
        • Activation of T-cell assisted by calcineurin and IL-2
    • CD28
      • Costimulatory signal from APCs such as B-cells
      • Binds to Ce
    • CD40-L
      • Attaches to B-Cell CD40 receptor
      • Important for T-Cell B-Cell

T-Cells can be divided into:

  • CD4+ T Cells - Helper Cells
    • CD4 molecule is present

    • Subtypes

      T Cell typeReactionSecretion of
      Th1Type IV HRIL2 and IFN gamma
      Th2Type I HRIL-4 and IL-5
      Th17Responsible for Fungal infections and autoimmune disordersIL-17

  • CD+ T-cells - Cytotoxic
    • CD8 positive
    • Binds to MHC Class I

| CD4:CD8 | 2:1 | | —–– | — |

Activation of Immune System

  • Antigens are divided into
  • Proteinaceous antigens

    • T-Cell dependent
  • Carbohydrate/Lipid Antigens (non-proteinaceous)

    • T-Cell independent
  • Antigen presenting cells internalize antigens and process it

  • APCs then express the antigenic peptide through the MHC molecule

  • MHC molecule is responsible for attachment of antigenic peptide

  • Then APCs enter the systemic circulation and lymphatic circulation

  • Clonal Selection occurs:

    • Only a few T-cells come in contact with specific antigen peptides presented by the APC depending upon the specific antigen

T-cells:

  • Effector T-cells
    • Deals with the presentation
  • Memory T-cells
    • These remain dormant after developing antigen receptor
    • Deals with later infection
    • These are fewer in number
    • CD45RO is used to detect memory T-Cell
      • CD45 is present on leukocytes
      • Mem OR y - Memory device

APCs:

  • APCs internalize internal/external peptides (after being broken down)
  • The MHC chains produced by the Endoplasmic Reticulum is expressed on the APC surface along with the peptide in

Professional APCs

  • These APCs have a very high expression of MHC 1
  • Dendritic Cells

    • Langerhans cells (tissue resident macrophage) - Skin and Interstitial Cell
    • Follicular dendritic cells - reservoir for HIV present in - Lymph node and spleen
  • B-Cells

    • Activated B-cells turn into plasma cells -> secrete antibodies
  • Macrophages

    [[Pasted image 20210701093452.png]]

    • CD13, CD14, CD15 and CD33 are CD markers

Non-Professional APCs

  • These are non-standard APCs with low but significant expression of MHC
  • Fibroblasts
  • Endothelia Cells
  • Thymic epithelial cells
  • Glial Cells
  • Pancreatic Beta-Cells

MHC

Major Histocompaitibility Complex Also known as HLA - Human Leukocyte Antigen

  • The gene encoding is present on short arm of Chromosome 6p [[Pasted image 20210710123112.png]]
  • Class I region codes for MHC I
    • MHC I is present in all nucleated cells and Platelets
  • Class II region encodes for MHC II
    • MHC II is present in all APCs
  • Class III region codes for
    • C2
    • C4
    • Properdin
    • TNF-alpha
    • 21-alpha hydroxylase
  • Cell Activated - immune cell activated
  • Ag Binding Cleft

MHC Class I

  • Made of 3 alpha chains and 1 beta chain
  • Antigenic cleft is present in between alpha 1 and alpha 2
  • Alpha 1 and alpha 2 are distal alpha chains
  • Alpha 3 is proximal alpha chain

Distal chains form the antigen binding cleft

  • CD8+ T-cells bind to MHC Class I - Endogenous Antigens

MHC Class II

  • Made of two alpha and two beta
  • Antigenic cleft is present in between Beta 1 and Alpha 1
  • Beta 1 and Alpha 1 are distal chains
  • MHC Class I is detected by Alloantiserum
  • MHC Class II is detected by Mixed Lymphpcyte Reaction
  • CD4+ T-cells bind to MHC Class II - Exogenous Antigens
  • Most antigens bind to MHC class II

Clinical Relevance Of MHC

  • Genetic Association of Disease
    • HLA - DR3/DR4 of class II region is associated with Type 1 Diabetes Melitus 2
    • HLA - B27 of Class I region is associated with Ankylosing spondytis 3
  • Organ Transplantation
    • Gene match of HLA is done to ensure compaitibility
    • Tissue typing is done by:
      • Mixed Lymphocyte Reaction (the same test for MHC II)
      • Micro-cytotoxicity assay
      • Nowadays HLA molecular matching is done
  • Paternity Disputes

T-Cell Activation

  • There are 2 signals involved
    • Primary Signal/Signal 1
      • MHC II binding to CD4 receptor
    • Co-stimulatory signal
      • CD28 on T cell with B7
        • B7a - CD80
        • B7b - CD86
    • Both signals are required for T-cell activation

      • External antigen provides both signals
      • Self antigens however only provide primary signal
        • Co-stimulatory signal is not generated - ANERGY
        • This property is known as: Tolerance is exhibited by Self-antigens
    • Negative co-stimulatory signal may also be received

      • Negative co-stimulatory signal delivery molecules - usually present in self-antigens
      • It reduces T-cell activation
        • CDLA-4
        • PD-1
      • B7.1 and B7.2 interact with this
Footnotes
1.
Major Histocompaitibility Complex
2.
Pancreas produces little to no insulin
3.
A type of arthritis in which there is a long-term inflammation of the joints of the spine. Typically the joints where the spine joins the pelvis are also affected. Occasionally other joints such as the shoulders or hips are involved. Eye and bowel problems may also occur. Back pain is a characteristic symptom of AS, and it often comes and goes. Stiffness of the affected joints generally worsens over time.