Showing posts with label immunology. Show all posts
Showing posts with label immunology. Show all posts

Impaired regulation of the immune response

CLONAL DISORDER
  • Multiple myeloma
    • Overproduction of specific monoclonal antibody
    • Impaired function of the rest of hum oral immune system
  • Paroxyamal nosturnal haemoglobinuria (PNH)
    • Impaired production of molecules involved in contra of complement activation
      • DAF
      • CD59
    • Complement → RBC lysis →Haemolytic anaemia

AUTOIMMUNITY
  • Impared regulation of humoral immunity → Production of auto reactive antibodies (autoantibodies)
  • vs: Receptors, DNA or othe intranuclear antigens, plasma proteins and macromolecules
  • Autoreactive T lymphocytes also produced.

Adaptive Immunity

  • Humoral immunity
    • Complement system, antobodies
  • Cellular immunity
    • T-Lymphocytes

ANATOMY OF THE ADAPTIVE IMMUNE SYSTEM
  • Stem cells of bone marrow → red cells, leucocytes, B cells 
  • Thymus → T cells
    • Thymus
      • Anterior mediastinum. Grows in childhood. Gradual involution after puberty. Continue to function during adult life. 
      • Immature T cells in cortex. Mature T cells in medulla
  • Lymph nodes, Spleen, Mucosal-associated lymphoid tissue (MALT)
  • Lymph nodes
    • Comprise a cellular cortex
    • Lymphocytes  → High endothelial venules → Spleen, Lymph node
    • B and T cells continue to recirculate through lymph node
    • B cells 
      • B cells organised into follicles
      • Active immune response → B cells → Follicles → Germinal centres
      • B cells → Medulla → Plasma cells → Antibody
    • T cells 
      • In deep cortex
    • Antigen-presenting cells in B and T cells areas
  • Spleen
    • White pulp
      • Organisation similar to B cell follicle and T cells areas
    • Red pulp
      • Blood vessels network removing old red blood cells
  • MALT
    • GIT: Peyer's patches in small intestine
    • Respiratory tract: Tonsils. Adenoids
    • Urogenital tract

B CELLS
  • Bone marrow-derived 
  • For humoral antibody immune response
  • Antigen → B cells + T helper cells → Immune response → Immunoglobulin production IgM IgG
  • Autoimmunity: Impaired mechanisms → Self-reactive antibodies

T CELLS
  • Recognise and discriminate antigens
    • Receptors
    • Antigen recognition: Petide fragments + HLA (human leucocyte antigen) molecules (clases I & II)

Innate Immunity

ACUTE PHASE RESPONSE
  • Cytokines → Liver hepatocytes → Proteins
  • Cytokines
    • Interleukin (IL)-1. Tumour Necrosis Factor (TNF). IL6
  • Proteins
    • Complement protein C3. Serum amyloid P component, C-reactive protein (CRP), Mannose-binding lectin, Lysozyme, Soluble CD14
  • Defence and repair
  • Autoimmune diseases: Chronic production of cytokines

TOLL-LIKE RECEPTORS (TLR)
  • Receptor for endotoxin
  • e.g. TLR-4
  • Bacterial: Lipopeptides, flagellin, hypomethylated DNA.
  • Fungal: Zymozan
  • Viral: Single-stranded or double stranded viral RNA)
  • Expressed on leucocytes and parenchymal cells
  • Ligation → Release of pro-inflammatory cytokines
  • Effects on adaptive immune response via 
    • Activation of antigen-presenting cells: Dendritic cells
    • B-cells
    • T-cells

LOCAL INFLAMMATORY RESPONSE
  • Dilatation & increased permeability of microscopic vessels
  • Endothelial activation → Adhesion of white blood cells
  • Atraction & activation of phagocytic cells: Neutrophils & mononuclear cells

Immune System Components

  • Barriers protecting against external injury
    • Skin
      • Sweats is acidic
      • Epidermis has low pH
    • Gut and respiratory tract
      • Mucus traps, solubilises and disposes unwanted foreign materials
  • Macromolecules
    • Proteins in extracellular fluid
  • Highy specialised cells 
    • Recognition and elimination
  • Innate/ Natural
    • Available the first time on encounter
    • No previous exposure
    • Not modified by repeated exposure
  • Adaptive/ Acquired
    • Modified after exposure
    • More active on repeated exposure

Autoantibodies

Scl-70 antibody is associated with diffuse systemic sclerosis.

Anticentromere pattern is associated with limited systemic sclerosis.

Ro antibody is common in patients with primary Sjogren's syndrome and systemic lupus erythematosus (SLE).

Jo-1 may be positive in patients with polymyositis.

Memory T cells

Memory T cells are generated after a primary immune response and allow a more rapid response when the same antigen is subsequently encountered. Cell surface markers characterising memory cells include CD45RO+ and CD44high.

The situation is becoming increasingly complex due to the recognition of several layers of T cell heterogeneity. The chemokine receptor CCR7 has been shown to further divide memory T cells into true memory cells (CCR7+) and 'effector' memory cells (CCR7-), with the latter circulating through peripheral tissues, and the former through lymphoid tissue.

Priming of naïve T cells in renal transplant

Priming of naïve T cells is carried out in local lymph nodes by professional antigen presenting cells such as dendritic cells. In the case of a renal transplant this may occur by T cells recognising donor MHC on donor dendritic cells transferred with the graft (direct pathway). It may also occur by the recognition of peptides derived from donor MHC molecules, presented on recipient MHC on recipient antigen presenting cells (indirect pathway).

Diagnosis of penicillin allergy

A history of penicillin allergy is relatively common in hospital patients, and is in most not due to type I hypersensitivity reactions.

A diagnosis of penicillin allergy crucially requires a detailed history of the drug reaction, and can be confirmed by a positive skin prick test to the major and minor determinants of penicillin. Skin prick testing is carried out if there is a clinical need for penicillin treatment e.g. treatment of infective endocarditis. A patient is unlikely to develop anaphylaxis with a negative penicillin skin prick test. The detection of penicillin specific IgE in the serum is unreliable.


Further Reading

Clinically useful monoclonal antibodies in treatment

Basiliximab and dacluzimab are antibodies to the IL2 receptor (CD25) expressed on activated T cells. They are used as induction therapy in renal transplantation.

Antibodies to CD3 (OKT3) are used in the treatment of renal transplant rejection.

Rituximab is an antibody to CD20 expressed on B cells and is used in B cell lymphomas.

Antibodies to CD154 (CD40 ligand - a molecule pivotal in T cell costimulation) had great promise in transplantation and autoimmunity. However, trials in humans have stopped after early work showed a high incidence of thrombosis, probably because CD154 is expressed on activated human platelets.

Antibodies to CD8 have not been used clinically.

T Cells

T-helper cells are distinguished by the presence of CD4 on their surface and their ability to recognise peptides presented on MHC class II molecules. Their functions include promoting delayed-type hypersensitivity reactions, characterised by monocyte recruitment, and providing help for B-cell antibody production.

Cytotoxic T cells have CD8 on their surface and recognise peptide presented on MHC class I molecules.

Common Drug Side Effects

mouth ulcers and methotexate

striae and steroids

argyria and silver-based preparations

hair loss and oral contraceptive

erythema multiforme and ampicillin.

Leukotriene

Leukotriene B4 is the most important of several leukotrienes produced by mast cells during early inflammation. It is produced from arachidonic acid, which is itself derived by phospholipases from phospholipids, and it acts by binding the high affinity receptor LTB1.

Paget's disease

Paget's disease of bone is a focal disorder of bone remodelling characterized by an increase in the number and size of osteoclasts in affected skeletal sites while the rest of the skeleton is spared.

Paget’s disease most commonly involves the axial skeleton, the pelvis being the most common, but it can affect any area. In the majority of patients, the disease affects at least two bones, but in one third of patients only one bone is affected. In the skull, the 8th nerve can be compressed, resulting in hearing loss. This is one of the more common complaints, being present in 37% of respondents in a recent survey of 2000 patients with Paget's disease . Other causes of hearing loss include pagetic involvement of the middle ear ossicles, which dampens the motion of these ossicles.

Unlike osteoarthritis, pagetic bone pain usually increases with rest, on weight bearing, when the limbs are warmed, and at night. An estimated 70% of patients who have Paget’s disease have no symptoms. The diagnosis is typically found incidentally on radiographs and laboratory investigations.

Fig 1: Osteoblasts and Osteoclasts
Fig 1: Paget's Disease of Bone
Fig 2: "Cotton Wool' appearance of Paget's Disease
Source: Fig 1Fig 3,