Primary immunodeficiency: Inherited or congenital. Part of the immune system is missing or does not function properly. Caused by defects in immune cell development or mutation in particular molecules.
Severe form:present in early life.
Less severe forms:may not cause problems until later in life.
Secondary immunodeficiency: previously functional immune system compromised by factors outside the immune system, such as viruses, aging, radiation, malnutrition, severe stress, splenectomy, thymectomy or chemotherapy.
More common than primary immunodeficiency.
From Immunobiology, Janeway et al. ADA: Adenosine Deaminase PNP: Purine nucleoside phosphorylase
DiGeorge’s Syndrome : thymic hypoplasia or aplasia resulted from dysmorphogenesis of the third and fourth pharyngeal pouches during early embryogenesis.
Nude Mice or Rats.
SICD: Mice: Lack Rag
Bubble Boy: Lack c
The main features of antibody deficiency Defective antibody production becomes critical 4-6 months after a full-term delivery when the maternally-derived IgG waned. The main manifestations are recurrent respiratory tract infections Defective CD40 ligand expression by T cells: no class-switching from IgM and no germinal centers. BtK deficiency: X-linked agammaglobulinaemia due to failure of B cell lymphopoiesis. Clinically antibody deficiency is secondary to lymphoid malignancies: myeloma and chronic lymphocytic leukaemia. The main features of T cell deficiency Defective T cell deficiency Increase in opportunistic infections: Pneumocystis carinii and Cryptosporidium . Mucosal yeast infection Defects in T-dependent antibody responses Di George syndrome HIV infection Defects in RAG genes, IL-2 receptors, and expression of MHC antigens. The main features of defects in neutrophils Severe invasive bacterial (mostly gram negative) infections that respond poorly to antibiotics and are often lethal and invasive fungal infection. Impairment of haemopoiesis Acute myeloblastic leukaemia: there is no stroma for neutrophil generation Cytotoxic drugs in cancer therapy -2 integrin deficiency: inability of neutrophils to migrate. The main features of defects in complement Deficiency of C3: recurrent bacterial infections and infants are usually lethal. Deficiency of C5-9: normal health. Only increased risk of infection by particular bacteria
The pol region of the virion genome encodes a HIV protease that is an aspartyl protease. Important for processing of essential functional protein products during the maturation of the virion. If the gag/pol polyprotein polyproteins are not cleaved, the virus fails to mature and is incapable of infecting a new cell.
Structural changes leading to increase in blood flow and extravasation of fluid. Emigration of cells of the acquired and innate immune systems to the site of injury through chemotaxis.
Elevated cellular metabolism and release of inflammatory mediators which promote local and systemic responses. Chemotactic factors to attract immune cells that invade surrounding tissues to fight infection (also cause damage).
Accomplished by specific inhibition or dissipation of the mediators. Growth factor will promote cell proliferation and repair.
Monocytes/Macrophages PMNs Edema Activity 1 2 3 REPAIR (fibroblasts) DAYS Kinetics of Inflammation
Redness ( ruber ): Dilation of capillaries Swelling ( tumor ): fluid containing plasma proteins and blood cells Heat ( calor ): increase in blood flow Pain ( dolor ): pressure on nerve; chemical mediators (e.g., bradykinin) Loss of function ( functio laesa ): the fifth cardinal sign was, supposedly, added by German pathologist Rudolf Virchow (1821-1902). Cardinal Signs of Inflammation First described by Celsus (not Celsius ) (10 BC-?)
Heat Redness Swelling Pain Loss of Function Nature Reviews/Immunology
Hypersensitivities Immune responses which are damaging rather than helpful to the host (In most cases). Trends Immunol. 2003 Jul;24(7):376-9. Gell and Coombs proposed a classification scheme which defined 4 types of hypersensitivity reactions : (P.G.H. Gell and R.R.A. Coombs, The classification of allergic reactions underlying disease. In: R.R.A. Coombs and P.G.H. Gell, Editors, Clinical Aspects of Immunology , Blackwell Science (1963)) The first 3 are mediated by antibody (Th2), the fourth by T cells (Th1). I IgE-mediated hypersensitivity (Anaphylactic) II Antibody-mediated cytotoxic hypersensitivity (Cytotoxic) III Immune-complex mediated hypersensitivity (Immune Complex) IV Delayed-type hypersensitivity ( DTH ) V(?) Granuloma (?)
Type I Hypersensitivity -Rapid ('Immediate or anaphylactic') allergic reaction. -Prior exposure to an antigen sensitizes a person to produce IgE. Re-exposure causes rapid degranulation of mast cells. The granule mediators causes acute inflammation: increase granulocytes, chemotaxis, and extravasation -Primary mediators (stored): Histamine and serotonin: vascular permeability, smooth muscle contraction ECF-A-Eosinophil Chemotactic Factor of Anaphylaxis NCF-A-neutrophil Chemotactic Factor of Anaphylaxis Protease: Mucus secretion, connective tissue degradation -Secondary Mediator (to be synthesized): Leukotrienes: vascular permeability, sm contraction Prostaglandins: vasodilation, sm contraction, platelet activation Bradykinin: vascular permeability, sm contraction, Pain Cytokines: numerous effects e.g.: Hayfever, asthma and allergic reaction to penicillin ( phenoxymethylpenicillin and benzylpenicillin). Expulsion of worms and insect infections. Tests: wheal-and-flare reaction (skin prick test for IgE) and RAST (radioallergosorbent test, blood allergen)
Type II Hypersensitivity -By specific antibody (IgM or IgG) binding to cells or tissue antigens. FcR causes ADCC Ab-dependent cellular immunity to bacteria and parasites Autoimmunity -By activating the classical complement pathway. Blood transfusion (ABO incompatibility reaction) IgM Rhesus disease (haemolytic disease of the newborn) IgG
Type III Hypersensitivity Immune complexes: IgG with soluble antigens. Similar to type I except that IgG is involved. Preformed immune complexes bind to the low affinity Fc RIII. Pulmonary reactions to inhaled antigens: Occupational related diseases: Farmer’s lung. The Arthus reaction A local type III hypersensitivity reaction in experimental models. Because the threshold for activation via Fc RIII is higher than for Fc RI, the reaction is slow (maximal at 4-8hrs) and more diffuse. Generalized or systemic reactions Large amount of soluble Ag-Ab complexes in circulation and deposition in various organs such as skin joints, kidneys and blood vessels. The deposition causes inflammation, lesions and infection. Rheumatoid Arthritis, Systemic lupus erythematosis, and serum sickness.
Type IV Hypersensitivity -Delayed type hypersensitivity (DTH) -Mediated by antigen-specific type I helper T cells, not Ab. APC (dendritic cells, or DC) present Ag in class II MHC groove, recognized by an antigen-specific T H 1 cell. Cytokines (IFN, TNF) and chemokines are produced. Macrophages, other T cells and, neutrophils accumulate to form granuloma. It is usually maximal at 48-72 hours. The classical example is in tuberculosis: tuberculin test ( Discovered by Robert Kock, 1905 Nobel Prize). Allergy to metal salts and small reactive chemicals coupled to hapten. Rejection of transplanted organs Skin contact reaction to poison ivy. http://www.info.gov.hk/dh/diseases/CD/photoweb
-Evolutionarily conserved. In insects, ensheathment reaction
In mammals, granulomas can be an immune reaction and are typified by the formation of epithelioid cells (modified macrophages).
Type 1 cytokine mediated such as TB.
Type 2 cytokine mediated such as Schistosome infection.
Summary of Hypersensitivity Reaction TYPE NAME INITIATION MECHANISM EXAMPLES I IgE-mediated hypersensitivity (Anaphylactic) 2-30 mins Ag cross-linking of IgE bound to mast cells; release of vasoactive mediators Systemic anaphylaxis, Local anaphylaxis, Hay fever, Asthma, Eczema II Antibody-mediated cytotoxic hypersensitivity (Cytotoxic) 5-8hrs IgG to cell-surface antigens; cell destruction via ADCC or complement ABO reactions; Rh in newborn; Autoimmune Haemolytic anemia III Immune-complex mediated hypersensitivity (Immune Complex) 2-8hrs Ag-Ab complex formed in serum and deposited in tissues; mast cell degranulation via Fc RIII; chronic inflam. Arthus reaction (Localized); autoimmune diseases IV Delayed-type hypersensitivity ( DTH ) 24-72hrs T H 1 cells release cytokines that recruit and activate macrophages Contact dermatitis, Tubercular lesions V Granuloma (?) Months to Years Formation of granuloma to encapsulate or isolate pathogens. Mediated by innate immunity or type 1 or type II cytokines TB, Schistosomiasis