anatomy
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WhiteBloodCellsImmunityImmuneDisorders-2.pptxWhite Blood Cells, Immunity & Immune Disorders
Srujana Rayalam DVM, PhD
Dept. of Pharmaceutical Sciences
PCOM-GA campus
PHAR 113G Anatomy, Physiology & Pathophysiology I
8/25/2020 4:05 PM
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Learning Objectives
Contrast the features of innate & acquired immunity
Contrast the features of humoral & cell-mediated immunity
Outline how B & T lymphocytes are able to recognize a diverse set of antigens
Describe how the second exposure to an antigen triggers a more robust response
Outline the key structural features and types of an antibody molecule
Outline the key products of the complement cascade & their roles in humoral immunity
Learning Objectives
Describe how an antigen-presenting cell triggers activation of a T lymphocyte
Contrast the roles of helper T cells & cytotoxic T cells in cell-mediated immunity
Describe tolerance and various types of immunizations
Describe the major types of allergies with examples (T cell and IgE mediated)
Outline the factors involved in the development of SCID and AIDS
Types of Immunity
Basic Immunology: Functions and Disorders of the Immune System; Fourth Edition; Abul K. Abbas et al.,
Host defenses are grouped under innate immunity, which provides immediate protection against microbial invasion, and adaptive immunity, which develops more slowly and provides more specialized defense against infections
Innate immunity
Provides general resistance to attack
not directed at specific disease organisms
Includes:
Destruction of microbes by acids & digestive enzymes in stomach
Resistance of skin to penetration by invading organisms
Substances in bloodstream
Lysozyme, complement complex, basic polypeptides etc
Players:
resident macrophages, granulocytes, monocytes and natural killer cells
Acquired (adaptive) immunity
Provides defense against specific organism or toxin
Develops only after initial attack by that specific agent
Players:
Antibodies
Activated lymphocytes
Very powerful defense against specific threat
Rationale for immunization
Types of Acquired Immunity
Humoral
Involves antibody generation against invading organism
Mediated by B lymphocytes
Cell-Mediated
Involves cells that target invading organism
Mediated by T lymphocytes
Both types are initiated by antigens
Types of Acquired Immunity…con’t
Active immunity:
Immunity developed by vaccination or infection
Passive Immunity:
Transfer of antibodies from immunized individuals to unimmunized individuals (Newborns: Placenta and breast milk)
Lymphocytes
Both T and B lymphocytes are derived from hemopoietic stem cells in bone marrow
Some migrate to thymus for differentiation or preprocessing
Designated as “T lymphocytes”
Others remain in bone marrow or migrate to liver for differentiation
Designated as “B lymphocytes” (B = bursa – specialized organ in birds)
The third category of lymphocytes are natural killer cells (NK cells)
Development of T and B Lymphocytes
Most preprocessing occurs before birth
Preprocessed T lymphocytes & B lymphocytes collect in lymphoid tissues
Guyton and Hall Textbook of Medical Physiology (12th edition)
Preprocessing of T lymphocytes
Occurs in thymus
Cells divide rapidly & develop extreme diversity for antigen recognition
Somatic recombination, V(D)J recombination
Each T lymphocyte develops specificity against one antigen
Thousands of distinct T lymphocyte clones develop
Recognize thousands of distinct antigenic epitopes
Thymus screens clones for reactivity against “self-antigens”
Clones with such reactivity (≈ 90% of clones) destroyed by phagocytosis
Remaining clones leave thymus & collect in lymphoid tissues
Preprocessing of B lymphocytes
Occurs in liver---in mid-fetal life
Bone marrow---late fetal life
Less understood than T lymphocyte preprocessing
B cells secrete antibodies and have greater diversity
Millions of distinct clones develop
Each B lymphocyte develops specificity against one antigen
Clones also screened for reactivity against “self-antigens”
After preprocessing migrate to lymphoid tissues
Preprocessing of T and B Lymphocytes
Role of Lymphocyte Clones
Millions of specific types of lymphocytes stored in the lymphoid tissue
Capable of forming only one type of antibody or one type of T cell with a single type of specificity
Remain dormant in lymphoid tissue until antigen exposure
Guyton and Hall Textbook of Medical Physiology (12th edition)
Activation of Preprocessed B & T Lymphocytes
Antigen exposure triggers rapid expansion of specific clone
T lymphocyte yields activated T cell
B lymphocyte yields plasma cell – latter produces antibody
Preprocessed B lymphocytes express antibody on cell surface
Antigen binding to antibody can activate B lymphocyte
Preprocessed T lymphocytes have receptor – T cell Receptor (TCR) on cell surface
Antigen must be “presented” in specific context by antigen-presenting cell
Macrophages typically phagocytose organism & present antigen to B & T lymphocytes
Humoral Immunity
Formation of antibodies by plasma cells
Antigen presenting cells and helper T cells activate B cells
Activated B cell – Lymphoblast – enlarged with high endoplasmic reticulum – differentiate into plasmablast
Plasmablast divide rapidly to produce plasma cell → produce antibodies at extremely rapid rate
Primary & Secondary Responses to Antigen
Requires plasma cell production from limited clone of B lymphocytes
Response typically delayed by >1 week
Response limited in magnitude
Response subsides quickly – plasma cells have short life span
Guyton and Hall Textbook of Medical Physiology (12th edition)
Antibody response to initial antigen exposure is slow & weak
Primary & Secondary Responses to Antigen
Much larger B lymphocyte clone due to memory B cells
Response occurs rapidly (often within hours)
Response substantially greater in magnitude
Response has prolonged duration
Second exposure to same antigen triggers much more robust response
Guyton and Hall Textbook of Medical Physiology (12th edition)
Immunization → accomplished by injecting antigen in multiple doses with periods of several weeks or several months between injections
Difference Between Primary Response and Secondary Response
Formation of Memory Cells
Some lymphoblasts do not form plasma cells but instead form new daughter cells that retain nature of original clone
Designated as “memory B cells”
Populate lymphoid tissue throughout body
Remain dormant until activated once again by a new quantity of the same antigen
Provide reservoir to combat future infection by same organism
Cause a much more rapid and much more potent antibody response because of many more memory cells than there were original B lymphocytes of the specific clone - secondary response
Structure of Antibody
Comprise disulfide-linked heavy & light chains
Most have 2 light & 2 heavy chains
Light & heavy chains arranged in parallel
Variable regions at N-termini define antigen binding pocket
Guyton and Hall Textbook of Medical Physiology (12th edition)
Classes of Antibodies
Immunoglobulin G (IgG): makes up75% of the serum Abs, Abs of secondary response
Immunoglobulin A (IgA): external secretions of body such as saliva, tears, breast milk, bronchial and intestinal mucus
Immunoglobulin E(IgE): allergic responses
Immunoglobulin M (IgM): primary immune response
Immunoglobulin D (IgD): present on surface of B lymphocytes along with IgM , role not clear
Mechanisms of Action of Antibodies
By directly attacking the invader
agglutination, precipitation, neutralization, opsonization and lysis
Agglutination
Clumping of large antigens (or pathogenic organisms) making them less immunogenic
Precipitation
Precipitation of soluble particles
Neutralization
Blocking the binding sites on viruses/neutralizing toxins etc
Activation of the “complement system”
Direct activation of effector cells
Basophils, mast cells, macrophages etc carry Fc receptors
Agglutination of Substance by Antibody
Guyton and Hall Textbook of Medical Physiology (12th edition)
Activation of Complement Cascade
Complement comprises system of ≈ 20 proteins (mostly zymogens) in plasma
Antigen–antibody reaction triggers classic pathway of complement activation
Cascade of zymogen → enzyme reactions leads to extensive amplification of effects
Guyton and Hall Textbook of Medical Physiology (12th edition)
Complement Cascade
Consequences of complement activation
Opsonization
Chemotaxis
Activation of effector cells
Lysis
Cell mediated immunity
Presentation of antigen to T lymphocyte in lymph tissue activates specific clone
Some daughter cells retain nature as original T lymphocytes – expanded in number
Designated as “memory T cells”
Populate lymphoid tissue throughout body
Provide reservoir to combat future infection by same organism
Guyton and Hall Textbook of Medical Physiology (12th edition)
Types of T lymphocytes
CD4 cells
CD8 cells
MHC-I
MHC-II
Antigen Presenting Cells (APC)
Macrophages
Dendritic cells in spleen and lymph nodes
Langerhan’s cells in skin
Antigen presented in association with major histocompatibility complex (MHC)
MHC I proteins present antigen to cytotoxic T cells (CD8)
MHC II proteins present antigen to helper T cells (CD4)
Cytotoxic T cell
Helper T cell
Mechanisms of T-cell-mediated cytotoxicity
Regulatory Role of Helper T Cell
Guyton and Hall Textbook of Medical Physiology (12th edition)
IL-2, IL-4, IL-5, IL-6
GM-CSF, interferon γ
Lymphokines enhance phagocytosis by macrophages
Cytotoxic and Suppresor T cells
Cytotoxic T cells (“killer T cells”)
Destroy invading organisms & virus-infected host cells
Perforins create holes in cell membrane of target - LYSIS
Induce apoptosis through death receptor pathway
Suppressor T cells
suppress functions of cytotoxic T cells & helper T cells
Keep immune response in check & contribute to immune tolerance
T lymphocytes: Summary
Basic Immunology: Functions and Disorders of the Immune System; Fourth Edition; Abul K. Abbas et al.,
Failure of the Tolerance Mechanism
Tolerance develops during preprocessing of T lymphocytes in the thymus and of B lymphocytes in the bone marrow
Loss of immune tolerance to ones own tissues - causes autoimmune diseases
Type-1 diabetes mellitus – autoimmune destruction of pancreatic beta cells that produce insulin
Lupus erythematosus - person becomes immunized against many different body tissues at the same time causing extensive damage and often rapid death
Myasthenia gravis - immunity develops against the acetylcholine receptor proteins of the neuromuscular junction, causing paralysis
Immune Disorders
Immunosuppressive response
Increased rates of infectious diseases
Immunostimulatory response
Hypersensitivity reactions
There are three types of immunological disorders
1. Hypersensitivity
2. Autoimmune disease
3. Immunodeficiency
Hypersensitivity
Most allergic reactions fall into one of four major types:
1. Type I: Immediate IgE-mediated
Pollen/Hay fever
2. Type II: Cytotoxic
Blood transfusion
3. Type III: Immune complex-mediated
Rheumatoid arthritis
4. Type IV: Delayed cell-mediated
Poison Ivy
Type 1 hypersensitivity reaction Allergy
IgE mediated
First exposure to antigen induces an IgE antibody response leading to sensitization
IgE antibodies bind to mast cell receptors and the individual is now “sensitized”
Overreaction to an allergen that comes in contact through skin, inhaled through lung, swallowed or injected.
Triggered by pollen, dust, animal danders, food, … can also occur as a result of drug or stings from insects.
During the subsequent exposures, antigens activate IgE antibodies on the mast cell causing it to degranulate
Histamines, eicosanoids and/or cytokines are released
Hives, hay fever, asthma and anaphylactic shock
Reactions generally occur within 30 minutes of exposure
Activated T Cell mediated
Delayed-reaction allergy is caused by activated T cells and not by antibodies
Repeated exposure to poison ivy – activates helper T cell – second exposure - these activated T cells elicit a cell mediated type of immune reaction
the cytokines cause inflammation which attracts WBC to the site
these then release chemicals that result in allergic dermatitis or contact dermatitis
Examples: poison ivy, poison oak and latex reactions
Type IV hypersensitivity reaction Allergy
Severe Combined Immunodeficiency Disease
Absence of normal thymic tissue
Lymph nodes, spleen, and other peripheral lymphoid tissues - devoid of lymphocytes
In these patients, the complete or near-complete failure of development of both the cellular and the humoral component of the immune system results in severe infections.
Defective cytokine signaling
Defective T cell receptor signaling
Defective receptor gene recombination
Acquired immunodeficiency syndrome
Chronic retroviral infection (HIV)
Retroviruses contain viral RNA that is transcribed by viral reverse transcriptase into double-stranded DNA
dsDNA is integrated into the host genome
Cellular activation leads to transcription of HIV gene products and viral replication
Lymph tissues become centers for massive viral replication
Progressive decline in CD4 helper T lymphocyte number and function
AIDS…cont’d
The marked decline in CD4 T-lymphocyte counts—characterizing HIV infection—is due to
direct HIV-mediated destruction of CD4 T lymphocytes
toxicity of viral proteins to CD4 T lymphocytes and hematopoietic precursors
induction of apoptosis (programmed cell death)
CD8 CTL activity is initially brisk and effective at controlling viremia but ultimately, viral proliferation outpaces host responses.
Overview
Innate vs acquired; cell mediated vs. humoral
Preprocessing of B and T lymphocytes
Primary exposure vs. secondary exposure
Structure and types of antibodies
Roles of complement system and APCs
Roles of helper T cells and cytotoxic T cells
Immunological disorders: hypersensitivity reactions
Key features of AIDS
