IMMUNOPATHOLOGY
DR.Hameed n.mousaFicms pathology
Head of depatment
. Learning objectives
At the end of the chapter, the student is expected to:1. Learn mechanisms and examples of hypersensitivity reaction
2. Understand etiologic factors in autoimmune diseases
3. Have bird’s eye view concept on immunodeficiency states
Introduction:
Immunity = protection against infections,immune system : is the collection of cells and molecules that are responsible for defending us against the countless pathogenic microbes in our environment.
Deficiencies in immune defenses: result in an increased susceptibility to infections, which can be
life-threatening if the deficits are not corrected.
On the other hand, the immune system is itself capable of causing great harm and is cause of some of the most vexing and intractable diseases of the modern world.
Thus, diseases of immunity range from those caused by "too little" to those caused by "too much or inappropriate" immune activity
Defense against microbes consists of two types of reactions: Innate immunity& Adaptive immunity
Innate immunity (also called natural, or native, immunity) is mediated by cells and proteins that are always present and poised to fight against microbes and are called into action immediately in response to infection.
The major components of innate immunity are:
epithelial barriers of the skin, gastrointestinal tract, and respiratory tract, which prevent microbe entry
phagocytic leukocytes (neutrophils and macrophages);
natural killer (NK) cell; a specialized cell type
complement system: circulating plasma proteins
• The major components of innate immunity are:
• Epithelial barriers of• the skin, gastrointestinal tract, and respiratory tract, which prevent microbe entry
• 2- phagocytic leukocytes (neutrophils and macrophages);
• 3- natural killer (NK) cell; a specialized cell type
• 4- complement system: circulating plasma proteins
Adaptive immunity (Also known as Acquired or Specific immunity, Immune system, & Immune response ).
Adaptive immunity is normally silent and responds (or "adapts") to the presence of infectious microbes by becoming active, expanding, and generating potent mechanisms for neutralizing and eliminating the microbes.
The components of the adaptive immune system are lymphocytes and their products.
The components of the adaptive immune system are lymphocytes and their products
There are two types of adaptive immune responses:
humoral immunity, mediated by soluble antibody proteins that are produced by B lymphocytes (B cells) (Antibodies provide protection against extracellular microbes in the blood, mucosal secretions, and tissues.), and cell-mediated (or cellular) immunity, mediated by T lymphocytes (also called T cells)
T lymphocytes are important in defense against intracellular microbes. They work by either:
* -directly killing infected cells (accomplished by cytotoxic T lymphocytes)
*-or by activating phagocytes to kill ingested microbes, via the production of soluble protein mediators called cytokines (made by helper T cells).
• 1.T-lymphocytes (thymus derived ) T (thymus-derived) lymphocytes express antigen receptors called T cell receptors (TCRs) that recognize peptide fragments of protein antigens that are displayed by MHC molecules on the surface of antigen-presenting cells.
• constitute 60 -70 % of peripheral lymphocytes
• CD4 helper ,inducer 60 % of T cells.
• CD8 cytotoxic ,suppressor 30 % of T cells.
• CD4 :CD8 2:1 in normal healthy person
• CD4 Class II MHC.
• CD8 Class I MHC.
• Effector CD4 (TH1) secret IL-2 &IFN-8.
• (TH2 ) secret IL-4 ,IL-5 &IL-10.
• Cellular immunity
Cells Of The Immune System
• 2. B- lymphocytes (Bone marrow derived ) express membrane-bound antibodies that recognize a wide variety of antigens.
They constitute 10-20 % of peripheral lymphocytes
On antigenic stimulation B-cells differentiated to
plasma cell
secrete immunoglobulin
humoral immunity
5 types of Ig (IgG ,IgM ,IgA ,IgE & IgD)
• 3.Macrophages (express class II MHC)
• 4.Dendritic cells ( antigen presenting cell “APC”)• interdigitating D.C.
• Langerhan’s Cell (skin).
• Follicular D.C.
• 5.Natural killer (NK) cells
• kill cells that are infected by some microbes, or are damaged beyond repair.
• NK cells express inhibitory receptors that recognize MHC molecules that are normally expressed on healthy cells, and are thus prevented from killing normal cells
• Constitute 10-15% of peripheral blood lymphocytes
Soluble mediators of the immune system
1.Cytokines that mediate natural immunity(IL-1, TNF-α, type I –IFN & IL-8 ).
2.Cytokines that regulate lymphocytes growth activation & differentiation.
3.Cytokines that activate inflammatory cells.
4.Cytokines i.e. stimulate haematopoiesis (CSF , GM-CSF.)
5.Cytokines therapy of cancer (immunotherapy).
6.Chemokines:
induce their effect autocrine.
paracrine.
endocrine.
Cytokines
It is the antigens responsible for the rejection of transplanted organs.
Based on their chemical structure ,tissue distribution & function . MHC gene products fall in to 3 categories :
1. Class I MHC [HLA-A,HLA-B,HLA-C]
CD8 +T-cell class I MHC
2. Class II MHC [HLA-D [ DP,DQ,DR]
CD4+T-cell class II MHC
3. Class III molecules [complement C2,C3&BF] they don't act as histocompatibility (transplantation).
(MHC=Major histocompatibility complex =(HLA)
Histocompatibility A.g.
Figure 5-3 Lymphocyte antigen receptors. A, The T-cell receptor (TCR) complex and other molecules involved in T-cell activation. The TCRα and TCRβ chains recognize antigen (in the form of peptide-MHC complexes expressed on antigen-presenting cells), & the linked CD3 complex initiates activating signals. CD4 and CD28 are also involved in T-cell activation. (Note that some T cells express CD8 and not CD4; these molecules serve analogous roles.) B, The B-cell receptor complex is composed of membrane IgM (or IgD,) & the associated signaling proteins Igα and Igβ. CD21 is a receptor for a complement component that promotes B-cell activation.
organ transplantation.
induction & regulation of immune response especially HLA Class II .
paternity test.
HLA & Disease Association e.g.ankylosing spondylitis HLA-B27
SIGNIFICANCE OF MHC MOLECULES
Adaptive immune responses consist of sequential phases: recognition of antigen by specific lymphocytes, activation of lymphocytes (consisting of their proliferation & differentiation into effector cells), & the effector phase (elimination of antigen). The response declines as antigen is eliminated, & most of the antigen-stimulated lymphocytes die by apoptosis. The antigen-specific cells that survive are responsible for memory. The duration of each phase may vary in different immune responses. These principles apply to humoral immunity (mediated by B lymphocytes) and cell-mediated immunity (mediated by T lymphocytes
Cell-mediated immunity. Naive T cells recognize MHC-associated peptide antigens displayed on dendritic cells in lymph nodes. The T cells are activated to proliferate (under the influence of the cytokine IL-2) and to differentiate into effector and memory cells, which migrate to sites of infection and serve various functions in cell-mediated immunity. Effector CD4+ T cells of the TH1 subset recognize the antigens of microbes ingested by phagocytes and activate the phagocytes to kill the microbes and induce inflammation. CD8+ CTLs kill infected cells harboring microbes in the cytoplasm. Not shown are TH2 cells, which are especially important in defense against helminthic infections. Some activated T cells differentiate into long-lived memory cells. APC, antigen-presenting cell.
Humoral immunity. Naive B lymphocytes recognize antigens, and under the influence of helper T cells), the B cells are activated to proliferate and to differentiate into antibody-secreting plasma cells. Some of the activated B cells undergo heavy-chain class switching and affinity maturation, and some become long-lived memory cells. Antibodies of different heavy-chain isotypes (classes) perform different effector functions, shown on the right.
SUMMARY Overview of Normal Immune Responses
The physiologic function of the immune system is defense against infectious microbes.The early reaction to microbes is mediated by the mechanisms of innate immunity, which are ready to respond to microbes.
These mechanisms include epithelial barriers, phagocytes, NK cells, and plasma proteins, e.g., of the complement system.
The reaction of innate immunity is often manifested as inflammation.
SUMMARY: Overview of Normal Immune Responses ( cont’d )
The defense reactions of adaptive immunity develop slowly, but are more potent & specialized.
Microbes & other foreign antigens are captured by dendritic cells & transported to lymph nodes, where the antigens are recognized by naïve lymphocytes.
The lymphocytes are activated to proliferate & differentiate into effector & memory cells.
Cell-mediated immunity is the reaction of T lymphocytes, designed to combat cell-associated microbes (e.g., phagocytosed microbes & microbes in the cytoplasm of infected cells.
SUMMARY: Overview of Normal Immune Responses
Humoral immunity is mediated by antibodies & is effective against extracellular microbes (in the circulation and mucosal lumens).CD4+ helper T cells help B cells to make antibodies, activate macrophages to destroy ingested microbes, & regulate all immune responses to protein antigens.
The functions of CD4+ T cells are mediated by secreted proteins called cytokines.
CD8+ cytotoxic T lymphocytes kill cells that express antigens in the cytoplasm that are seen as foreign (e.g. virus-infected and tumor cells).
Antibodies secreted by plasma cells neutralize microbes and block their infectivity, & promote the phagocytosis & destruction of pathogens.
Antibodies also confer passive immunity to neonates.
• These may result from:
• Excessive immune responses (hypersensitivity reactions)• Unwanted or inappropriate immunes response ( Autoimmune diseases )
• Inadequate immune responses (immunodeficiency disease
DISORDERS OF THE IMMUNE SYSTEM