IMMUNOPATHOLOGY PT.2

• IMMUNOLOGIC TOLERANCE


  It is the phenomenon of unresponsiveness to an antigen induced by exposure of lymphocytes to that antigen.
• Self-tolerance 


  refers to lack of responsiveness to an individual’s own antigens, underlies the ability to live in harmony with the cells and tissue.
• Loss of self-tolerance


  is the underlying cause of autoimmune disorders.
• AUTOIMMUNE DISORDERS


  Immune reaction against self-antigens.
• Requirements to be considered in assessing autoimmune disease:

  1.) Presence of Immune Reaction specific for self-antigen

  2.) Evidence that such reaction is not secondary to tissue damage but is of primary pathogenic significance.

  3.) Absence of another well-defined cause of the disease.
• AUTOIMMUNE DISORDERS can be

  • organ-specific
  • generalized (SLE)
• Disorders in which chronic inflammation is prominent, it can be grouped under, immune-mediated inflammatory disease they may be autoimmune or the immune response may be directed against normally harmless microbes.
• Classification of Immune Tolerance

  1. Central tolerance
  2. Peripheral tolerance
• CENTRAL TOLERANCE

  Death of the self-reactive T-lymphocyte and B-lymphocytes are killed or rendered harmless during their maturation in the generative lymphoid organs (thymus, bone marrow).
• AIRE (Autoimmune Regulator) is a protein that stimulates the expression of peripheral tissue-restricted self-antigens in the thymus, and is critical in the deletion of T-cells.
• AIRE mutation results to autoimmune polyendocrinopathy.
• Receptor Editing

  When developing B cells detect self-antigens, they reactivate the machinery of Antigen receptor gene and generate a new antigen receptor, not specific for self antigens.
• PERIPHERAL TOLERANCE

  Irreversible or prolonged functional inactivation of lymphocytes, rendering them deactivated.
• Mechanism of T-cell Anergy:

  • Inhibitory signals from receptors that are homologous to CD28 but opposite in function, these are CTL4-A which binds to B7 molecules, and PD-1 which binds to two widely expressed ligands.

  • B7 in APC is less favors CTL4-A binding (higher affinity), favoring inhibition of the cell.

  • B7 in APC increases during innate immune responses causing more engagement of the CD28, favoring activation
• Mechanism of B-Cell Anergy:

  • When B cells encounter self-antigens, they become non responsive to subsequent antigenic stimulation and excluded from the lymphoid follicle

  • B lymphocytes also express inhibitory receptors that play a role in limiting their activation and preventing responses to self-antigen.
• Autoimmunity arises from a combination of the inheritance of susceptibility genes, breakdown of self-tolerance, environmental triggers, which promote the activation of self-reactive lymphocytes. This makes autoimmune disorders multifactorial.
• Inflammation or an initial innate immune response.

  A strong stimulus for the subsequent activation of lymphocytes and the generation of adaptive immune response.
• Most autoimmune diseases are complex multigenic disorders.
• Association of HLA Alleles:

  • HLA-B27–Ankylosing Spondylitis

  • HLWA-BW47–21 hydroxylase deficiency

  • HLA-A–Hereditary Hemochromatosis
• Association of Non-MHC Genes:

  • PTPN22

  • NOD2

  • CD25 genes (IL-2 receptor), and IL-17 receptor α-chain
• PTPN22

  • Encodes for Tyrosine Phosphatase.

  • Associated with rheumatoid arthritis, Type 1 DM.

  • High prevalence.
• NOD2

  • Associated with Crohn’s Disease.

  • NOD receptors with this variant are ineffective at sensing gut microbes including commensal bacteria, resulting in entry of and chronic inflammatory response.
• CD25 genes (IL-2 receptor), and IL-17 receptor α-chain

  • Associated with Multiple Sclerosis
• Some microbes may express antigens that have the same amino acid sequences as self antigens; this may result to activation of self-reactive lymphocytes, a phenomenon called molecular mimicry.
• Autoimmune diseases tend to be chronic, sometimes with relapses and remissions, and the damage is often progressive.
• Epitope Spreading – an immune response against one self antigen causing tissue damage, releasing other antigens, and resulting in the activation of lymphocytes by these newly encountered epitopes.
• Chronic inflammatory diseases are caused by abnormal and excessive TH1 and TH17 response; examples are psoriasis, multiple sclerosis, inflammatory bowel diseases.
• CD8+ CRLs contribute to killing of cells such as β-cells in Type 1 diabetes.
• Some autoimmune diseases such as rheumatoid arthritis involve both antibodies and T-cell mediated inflammation.
• SLE is an autoimmune disease involving multiple organs, characterized by a vast array of autoantibodies, particularly antinuclear antibodies (ANAs), in which injury is caused mainly by deposition of immune complexes and binding of antibodies to various tissues.
• SLE may be:

  • Acute or chronic

  • Remitting and Relapsing

  • Often Febrile Illness

  • Injury to skin, joints, kidney, and serosal membranes.
• SLE predominantly affects women affecting 1 in 700 with 9:1 female to male ratio during women of child bearing age and reproductive age group. 1:2 ratio in childhood or age of 65 onwards.
• The hallmark of SLE is the production of autoantibodies.
• Indirect immunofluorescence is used to detect antinuclear antibodies
• The pattern of the immunofluorescence:

  • Homogenous or Diffuse Pattern

  • Rim or Peripheral Staining Pattern

  • Speckled Pattern

  • Nucleolar Pattern

  • Centromeric Pattern
• Homogenous or Diffuse Pattern – usually reflects the antibodies to chromatin, histones, and occasionally, double stranded DNA.
• Rim or Peripheral Staining Pattern – Indicative of antibodies to double stranded DNA and some nuclear envelope proteins.
• Speckled Pattern – presence of uniform or variable-sized speckles, most commonly observed pattern hence the least specific. It reflects the presence of antibodies to non-DNA nuclear fragments such as Sm antigen, ribonucleoprotein, and SS-A and SS-B reactive antigens.
• Nucleolar Pattern – refers to the presence of a few discrete spots, represents antibodies to RNA. This pattern is reported most often in patients with SLE.
• Centromeric Pattern – Patients with systemic sclerosis often contain antibodies for centromeres.