Immune disorders Flashcards
Immune Reactions
Immune system has numerous functions including
Prevention/defense from infection
Inactivation and clearance of foreign substances
Immune reactions can cause host tissue injury
Hypersensitivity reactions cause release of inflammatory mediators that lead to tissue damage and eventually can lead to scarring (repair)
Hypersensitivity Reactions
Type I – Immediate (anaphylactic)
Mediated by TH2 cell cytokines
Via IL-4 action on B cells get class switching to IgE
Via IL-5 get development and activation of eosinophils
Type II – Antibody-mediated
Secreted ***IgG and IgM antibodies participate directly in injury to cells
Type III – Immune complex mediated
IgG and IgM antibodies bind antigens and the antigen-antibody complexes deposit in tissues and induce inflammation
Type IV – Cell mediated
Sensitized T-lymphocytes (TH1, TH17 cells and CTLs)
hypersensitivity and granuloma
Type IV hypersensitivity
Type I Hypersensitivity Disorders
Anaphylaxis
Hypotension secondary to vasodilation that may lead to shock
Laryngeal edema that may lead to airway obstruction
Inflammation and tissue destruction leading to scarring
Asthma
Reversible bronchoconstriction
Mucous hyperplasia
Inflammation and tissue destruction leading to scarring
Urticaria
Dermal angioedema with wheals
Itching
Food allergies
Increased intestinal peristalsis
Inflammation and tissue destruction leading to scarring
Allergic rhinitis and sinusitis
Mucous hyperplasia
Inflammation and tissue destruction leading to scarring
Type I Immediate Hypersensitivity
Immediate phase: *** 5 to 30 minutes post exposure
for about an hour
Dilated leaky vessels –> edema
Contraction of smooth muscle
Increased mucus production
Late phase: **2 to 24 hours later and may lasts days
Inflammation with eosinophilia–> tissue injury
petechiae and echymoses, what do you start to think?
platelets and/or von Willebrandt’s
granulomas associated with?
Type IV- cell mediated hypersensitivity (activated T lymphocytes)
Type II hypersensitivity
Type II- antibody mediated. IgG or IgM binding
good pasture syndrome
Mechanisms of type I hypersensitivity
Early - TH2 activation IgE class switch in B cells IgE release of mediators from mast cells
Later - TH2, epithelial and mast cells secrete IL-5 and eotaxin → eosinophils → enzyme (major basic protein and cationic protein) release → tissue destruction
signs/ symptoms of anaphylaxis
lightheadedness SOB, stridor skin-- hives, itchiness, flushing Heart-- fast or slow, low blood pressure swelling of lips, tongue and/or throat
Mast cell secretagogues
IgE (via Fc receptors), Anaphylatoxins C5a, C4a and C3a –> Mast cell –> Eosinophil chemotactic factor
among many other things
Urticaria
dermal hyperpermeability & wheals
angioedema
edema of dermis, mucosae and deeper tissues
hereditary angioedema
autosomal dominant C1 inhibitor deficiency
asthma
reversible airway obstruction
autoimmunity
reactions against an individual’s own tissues and cells
types 2,3, and/or 4
Placental transfer in autoimmune disorders
Maternal igG antibodies
thyroid hormone receptor –> graves
RBCs–> hemolytic anemia
platelets–> thrombocytopenia
acetylcholine receptor–> myasthenia gravis
Ro & La–> Cutaneous lupus & heart block
HLA alleles and the diseases
Rheumatoid arthritis- DR4 Type 1 diabetes DR3/DR4 Ankylosing spondylitis- B27 Postgonococcal arthritis-- B27 Autoimmune hepatitis- DR3 Primary Sjogren syndrome- DR3
Non-HLA genes associated with autoimmune diseases
PTPN22– protein tyrosine phosphatase
May affect signaling in lymphocytes
may alter activation of self-reactive T cells
Types II/III Antibody Mediated Hypersensitivity
Antibody-dependent complement-mediated cytotoxicity (Type II)
Classical complement cascade activation leads to lysis of cells
Direct lysis via membrane attack complex (C5b - C9), punches holes in cell
Mechanism normally used for killing Neisseria spp. bacteria
Antibody-dependent cell-mediated cytotoxicity (Type II)
Binding of antibody leads to activation of macrophages, neutrophils, eosinophils, natural killer cells, etc. that lead to cell injury and death
Mechanism normally used for killing other microorganisms, etc
Antibody-dependent cellular dysfunction (Type II)
Antibody binding causes abnormal cellular function (e.g. Graves disease)
No normal use for this mechanism
Antigen-antibody complex mediated attack on host tissues (Type III)
Antigen-antibodies complexes deposit or are initiated in tissue
Complement is activated (C5a attracts infl. Cells, C3a and C5a cause local vasodilation, etc.)
No normal use for this mechanism
Mechanisms of Antibody-mediated Injury
Antibody-dependent complement-mediated cytotoxicity
e.g. ABO incompatibility
Antibody-dependent cell-mediated cytotoxicity
e.g. killing virally infected cell
Autoimmune hemolytic anemia - mechanism
opsonization and phagocytosis of red cells
direct hemolysis via complement with ABO mismatch
Immunologic Thrombocytopenic Purpura
Spleen: normal size, congested sinusoids, prominent germinal centers, occasional megakaryocytes
Marrow: increased megakaryocytes
Peripheral blood: megathrombocytes
Goodpasture Syndrome
Diagnose = linear fluorescence
Antigen hidden in type collagen IV—exposed by smoking, solvents etc.
antigen and manifestation: SLE
lupus
nuclear antigens
nephritis, skin lesions, arthritis
antigen and manifestation: poststreptococcal glomerulonephritis
streptococcal cell wall antigen
nephritis
antigen and manifestation: polyarteritis nodosa
Hep B virus antigens (some cases)
Systemic vasculitis
pulmonary arteries are NOT involved
antigen and manifestation: Reactive arthritis
Bacterial antigens
acute arthritis
antigen and manifestation: serum sickness
foreign serum protein
arthritis, vasculitis, nephritis
antigen and manifestation: arthus reaction
injected foreign proteins
cutaneous vasculitis
acute proliferative glomerulonephritis
can be post infectious (strepto, staphylo, virus)
Immune complexes formed in circulation or on membrane, c3 deposited before others
Rheumatoid arthritis
citrullinated self proteins?
chronic arthritis
MS
antigens to myelin basic protein
myelin destruction by activated macrophages
demyelination in CNS
Type 1 diabetes mellitus
antigens of pancreatic islet beta cells
destruction of islet cells by CTLs
insulitis, destruction of beta cells
inflammatory bowel disease
chronic intestinal inflammation
Th1 and Th17 cytokines
psoriasis
plaques in the skin
Th17 cytokines
contact sensitivity
environmental antigens, poison ivy, etc.
skin rash and blisters
Th1/ Th17? cytokines
Guillain Barre Syndrome
Often begins after an infection or vaccination
Ascending paralysis (also some sensory loss)
2-5 % mortality
20% disability
Increased CSF protein
Viral or bacterial disease or vaccination T cell mediated peripheral nerve demyelination
Segmental demyelination of peripheral nerves
Axons damaged when severe
Chronic inflammation—most intense in spinal and cranial nerve roots
Rheumatic fever
molecular mimicry
Acute Rheumatic Fever
Pericarditis
Myocarditis; Aschoff bodies, Anitschkow cells
Endocarditis
CREST syndrome associated with
centromeric (coarse speckled) staining
SLE, Drug-induced lupus associated with
Homogenous staining
histone antigens
Fine speckled staining associated with
non specific
systemic sclerosis antigens
DNA topoisomerase I
autoimmune myosiis antigens
histidyl-tRNA synthetase
Sjogren syndrome antigens
RNP
SLE antigens
pretty much everything
how many criteria make SLE?
4 or more of the 11
photosensitivity, hemolytic anemia, anti-dna antibody, antiphospholipid antibodies, false-positive for syphilis, e.g.
prevalence of stuff in SLE
hematalogic 100 arthritis 80-90 skin 85 renal 50-70 raynaud 15-40
SLE features
butterfly rash, fever, joint pain
LE bodies or hematoxylin bodies
cells that engulf these bodies are called LE cells
In situ immune complex formation antigens probably the most important
anti-phospholipid syndrome
thrombotic microangiopathy
recurrent miscarriages
Nuclear antigens: nucleosomes- DNA and histones
anti double stranded DNA
Smith antigen
Ro/SS-A, La/ SS-B
Kidneys (75% of patients have renal involvement)
Increased serum creatinine
RBCs and RBC casts in the urine
Sjogren syndrome
Mikulicz syndrome - lacrimal and salivary gland enlargement from any cause
Sicca syndrome
Keratoconjunctivitis sicca dry eyes with blurred vision, thick secretions in conjunctival sac
Xerostomia dry buccal mucosa, difficulty swallowing, buccal fissures
Dry nasal mucosa
SS-A (Ro) and SS-B (La)
Lip biopsy
Schirmer test
Systemic Sclerosis
polyarthralgia tight skin on hands and face telangiectasias difficulty swallowing morphea CD4+ lymphocytes stimulate fibroblasts and collagen formation
Anti-Scl-70- against nuclear topoisomerase
anti-centromere
90% anti-centromere in CREST
GI tract- esophagus most common
kidneys- intimal proliferation and thickening of arteries –> ischemia
CREST
calcinosis raynaud phenomenon esophagal dysmotility sclerodactyly telangiectasias
ANTI-Centromere antibody
Dermatomyositis
heliotropic rash
often associated with occult tumors
anti-Jo-1
Polymyositis
Autoimmune disease involving skeletal muscle without skin involvement
Mixed connective tissue disease
Ill-defined autoimmune disease with overlapping features
Transplantation
Mechanisms of rejection
T Cell related
Cytotoxic T lymphoctes–> parenchymal & endothelial cell injury
CD4+–> delayed hypersensitivity reactions
CD4+–> activation of macrophages
Antibody Mediated
Types of Rejection Hyperacute -preformed antidonor antibodies are present Acute cellular -(direct pathway) T cells of recipient recognize allogeneic (donor) MHC molecules on the donor’s APCs Acute humoral - (indirect pathway) exposure to the class I and class II HLA antigens of the donor graft may evoke antibodies and attack graft vessels (vasculitis) Chronic - (indirect pathway) recipient T cells recognize MHC antigens of the graft donor after they are presented by the recipient's own APCs and induce direct cell mediated inflammatory damage or production of circulating antibodies that cause vascular injury in graft
HIV phases
acute- similar to flu for a few weeks about 3-6 weeks post infection
middle chronic: asymptomatic for years, prolonged by HAART
AIDS fever, weight loss, diarrhea, generalized generalized lymphadenopathy, multiple opportunistic infections, neurologic disease, and secondary neoplasms or
transplant phases
0-3 days hyperacute
4 days to 6 months- acute
more than 6 months- chronic rejection
bone marrow transplant rejection
graft vs host diseases
Bruton
x linked agammaglobulinemia
males after 6 months bruton tyrosine kinase mutation decreased B cells no plasma cells no intestinal IgA (giardia infections) No Igs for opsonization of organizms (encapsulated bacteria)
DiGeorge
Thymic Hypoplasia
22q11
abnormal 3rd & 4th pharyngeal pouches
Thymus, parathyroids, some of the clear cells of the thyroid, and ultimobranchial body defects
Hypoparathyroidism with hypocalcemia can lead to tetany
Cardiac outlet defects
Facial abnormalities
Viral, fungal and protozoal infections
T-cell deficiency
Hyper IgM
Inability of helper T cells to induce IgG, IgA, and IgE formation
Common Variable Immunodeficiency
Absent plasma cells (maturation blockage)
No immunoglobulins
Normal numbers of other B cells
Isolated IgA deficiency
Low levels of secretory and serum IgA
Anaphylactic transfusion reactions to IgA in donor plasma
Immune disorders such as SLE and RA
complement deficiencies
C1 inhibitor = hereditary angioedema induced by stress or trauma
Episodes of edema affecting skin and mucosal surfaces
Life-threatening asphyxia
Nausea, vomiting, and diarrhea
Rx - C1 inhibitor concentrates
C5, 6, 7, 8, or 9 (attack complex) Recurrent neisserial (gonococcal and meningococcal) infections
Wiskott-Aldrich Syndrome
WASP (Wiskott-Aldrich syndrome protein) gene mutation
Thrombocytopenia, eczema & recurrent infections
Petechiae or purpura, hematemesis or melena, epistaxis
Recurrent infections, ending in early death
HIV immunity
1% of white Americans inherit two defective copies of the CCR5 gene and are resistant to infection
CDC AIDS-defining conditions
cervical cancer, invasive encephalopathy kaposi sarcoma lymphoma: burkitt, immunoblastic, primary of brain wasting syndrome
Major abnormalities of immune function in AIDS
selective loss of CD4+ helper T cell subset
susceptibility to opportunistic infections
susceptibility to neoplasms
hypergammaglobulinemia and circulating immune complexes
aids-related malignancy
B cell lymphoma
Amyloidosis
cross beta pleated sheet conformation
congo red stain
apple green birefringence
Classification of amyloidosis
primary- monoclonal plasma cell proliferations (immunoglobulin light chains, chiefly delta)
secondary- chronic inflammatory conditions (SAA)
chronic renal failure (beta two microglobulin)
alzheimer (APP)
type 2 diabetes (islet amyloid peptide)
systemic senile amyloidosis– transthyretin
medullary carcinoma of thyroid- calcitonin
