Hypersensitivity, Autoimmunity and Immunodeficiency Part 4 Flashcards
what are histocompatability molecules
- located on chromosome 6
- induce and regulate immune response
what do histocompatability molecules bind to
peptide of foreign proteins for presentation to appropriate T cells known as MHC restriction
what are human leukocyte antigen complex
MHC
highly polymorphic
where are class I MHC molecules HLA-A, HLA-B and HLA-C loci found
- found on all nucleated cells
- trans-membrane alpha glycoprotein chain with a beta2- microglobulin
class I MHC molecules react with what
antibodies and CD8+ T lymphocytes
Class I MHC molecules are effective against what
virus infected cells and are principal agents involved in transplant rejection
how do you identify Class I MHC molecules
standard serologic techniques used for identification
how are HLA-D identified
only by mixed lymphocyte reactions, and sub-regions
how are HLA-DP, HLA-DQ, HLA-DR indentified
by either standard serologic techniques or mixed lymphocyte reactions
where are Class II Antigens HLA Associations found
on immune competent cells, including macrophages, dendritic cells, Langerhans cells, B cells and some T cells
trans-membrane alpha chain and beta chain react with what
CD4+ T lymphocytes
what is the function of trans-membane alpha chain and beta chain
effective against exogenous antigens processed by antigen presenting cells
what are class III proteins
complememnt components (C2, C3 and Bf)
what do class III protein genes encdoe for
TNF
LT or TNF-B
***what diseases are associated with HLA types
- 90% of cases of Ankylosing spondylitis HLA-B27
- primary hemochromatosis HLA-A3
- 21- hydroxylase deficiency HLA-BW47
- Rheumatoid arthritis HLA-DR4
- insulin dependent diabetes mellitus HLA-DR2/DR3
- systemic lupus erythematosus HLA-DR2/DR3
- Uveitis HLA-B27
- Reiter syndrome (urethritis, conjunctivitis and arthritis) HLA-B27
what is amyloidosis
-is a generic term for a variety of proteinaceous materials deposited in tissue interstitum in a spectrum of clinical disorders
what do amyloids look like in an H and E stain
is an amorphous, eosinophilic hyalin extracellular substance
what happens as amyloidosis progress
get adjacent pressure atrophy of adjacent cells
what is amyloidosis composed of
nonbranching fibril proteins 7.5 to 10nm in width by EM
x-ray crystallography and infrared spectroscopy of amyloidosis show a characteristic of
crossed Beta pleated sheet conformation
what are minor components of all amyloid deposits (5%)
-a nonfibrillar pentagonal glycoproteins known as the P component and proteoglycans
what are the most 3 common amyloidosis
- AL (amyloid light chain) derived from plasma cells and contains immunoglobulin light chains
- AA (amyloid-assocaited) is a unique non-immunoglobulin protein made in the liver
- ABeta amyloid found in the cerebral lesion of Alzheimer disease
AL protein is made of what
complete immunoglobulin light chains, the NH2-terminal fragments of light chains or both
AL protein deposition is associated with what
some form of monoclonal B-cell proliferation as AL is produced by immunoglobulin secreting cells
AA amyloid fibril is composed of what
a protein of 8.5-kD molecular mass (76 aa resides) that does not have homology to immunoglobulins
when are AA proteins deposited
during chronic inflammatory states
AA amyloid fibrils are derived from what
a 12-kD serum precursor synthesized in the liver known as serum amyloid-associated protein (SAA)
what is transthyretin (TTR)
is a normal serum protein which binds and transports thyroxin and retinol
a mutatant TTR and its fragments are found deposited in a group of genetic disorders called
familial amyloid polyneuropathies
how does amyloid transthyretin (ATTR) differ from its normal counterpart
differs by 1 a.a
where is TTR found
in hearts of the elderly (senile systemic amyloidosis)
Beta2- microglobulin (class I MHC antigen) has been identified as what
the amyloid fibril subunit (AM2m) in amyloidosis in the synovium, joints, and tendon sheaths of 60% to 80% of patients on long term hemodialysis and are structurally similar to the normal protein
can the B2-microglobulin be filtered through the cuprophane dialysis membrane
no
what is the beta-amyloid protein
is a 4-kD peptide that constitutes the core of the cerebral Alzheimer plaques as well as the amyloid deposited in cerebral blood vessel walls of Alzheimer patients
ABeta protein is derived from what
-a larger transmembrane glycoprotein known as amyloid precursor protein (APP)
what are amyloid deposits derived from
diverse precursors like hormones such as procalcitonin and keratin
what are the classifications of amyloidosis
- systemic or generalized involves several organ systems
- localized where only one organ, such as the heart, are involved
- primary amyloidosis is associated with immunocyte dyscrasias
- secondary amyloidosis is a complication of chronic inflammatory or tissue destructive process
- hereditary or familial is a separate, heterogenous group with distinctive patterns of organ involvement
what are primary amyloidosis
systemic AL type
what is multiple myeloma associated from
- is an example of primary amyloidosis
- the Bence Jones proteins lambda and klight chains are produces as well as the M (myeloma) protein
6% to 15% of meyloma patients develop what
amyloidosis so other factors (amyloidogenic potential) plays a role
majority of patients with AL do not have what
overt B cell dyscrasia
what are reactive systemic amyloidosis
- systemic AA types
- secondary amyloidosis
what is a common feature of reactive systemic amyloidosis
protracted cell injury
what are common causes of reactive systemic amyloidosis
pre-antibiotic treatment for:
TB
Brochiectasis
Chronic osteomyelitis
what is reactive systemic amyloidosis
a common cause of post antibiotic
what are automimmune states of reactive systemic amyloidosis
- Rheumatoid arthritis seen in 3% of pts
- ankylosing spondylitis
- inflammatory bowel disease
- chronic skin infection as with “skin pippin”
- non-immunocyte derived tumors such as renal cel carinoma and Hodgkin disease
what is Heredofamilial Amyloidosis
- rare and in limited geographic areas
- autosomal recessive familial Mediterranean fever
what is Mediterranean fever
- fever with inflammation of serosal surfaces in Armenians, Sephardic Jews and Arabs
- systemic and AA
- gene has been cloned and produces pyrin
autosomal dominant familial disorders are characterized by what
deposition of amyloid in the peripheral and autonomic nerves, amyloidotic polyneuropahy found in Portugal, Japan Sweden and the US due to mutant tranthyretins (ATTR)
what are localized amyloidosis
-nodular masses found in lung, larynx, skin urinary bladder, tongue and around the eye
what do the nodules of localized amyloidosis look like
nodules rimmed by infiltrates of lymphocytes and plasma cells and the amyloid is AL
what are endocrine amyloid
-are microscopic deposits found in medullary carincoma of thyroid, islet tumours of panreases, phenochromocytomas and undifferentiated cancer of the stomach, islets of Langerhans in NIDDM
amyloid derived from polypeptide hormones or from
unique proteins such as islet amyloid polypeptide (IAPP)
what are senile systemic amyloidosis
-are systemic deposits of amyloid in patients in their 70s or 80s, but usually found in the heart with restrictive cardiomyopathy and arrhythmias senile cardiac amyloidosis
senile systemic amyloidosis are composed of what
normal transthyretin molecules
4% of black population in the US are carriers for the allele for what
a mutant form of transthyretin leading to cardiac amyloidosis
what is the pathogenesis of reactive systemic amylodosis
- results from long standing tissue injury and inflammation which leads to formation of elevated SAA levels by liver cells under influence of IL-6 and IL-1
- have enzyme defect resulting in incomplete breakdown of SAA by monocyte-derived enzymes, leading to the AA molecule formation
in immunocyte dyscrasias the course of the precursor protein is derived
in vitro by proteolysis of the immunoglobulin light chains
what is the pathogenesis of immunocyte dyscrasias
-defective proteolytic degradation has been evoked
secondary amyloid due to what
chronic inflammation found in kidneys, liver, spleen, lymph nodes, adrenals and thryoid as well as other tissues
where are immunocyte-associated amyloidosis found
heart, GI tract, respiratory tract, peripheral nerves, skin and tongue
-kidneys, liver and spleen
where do Familial Mediterranean fever show deposits
in kidneys, blood vessels, spleen, respiratory tract and sometimes the liver
iodine and surlfuric acid will lead to what color staining of amyloid
-mahogany brown staining of amyloid deposits on organ when deposits are too small to see grossly
with increased deposition of amyloid what will happen to the organ
will become enlarged with a gray color and a way firm consistency
histologically amyloid beigns between what
cells increasing to produce pressure atrophy of cells
what are the locations of immunocyte-assocaited form
-perivascular and vascular localization
what color do amyloids appear when stained with congo red
- pink or red color under polarized light
- the Congo red strained amyloid shows an apple green birefrigence shared by all forms of amyloid due to the crossed Beta-pleated configurations of the fibrils
what can confirm the presence of amorphous nonoriented thin fibrils
EM
what are initial symptoms of amyloidosis
weakness, fatigue, weight loss are initial symptoms
what are other symptoms of amyloidosis
-renal disease with nephrotic syndrome and RF, hepatosplenomegaly, cardiac abnormalities with restrictive cardiomyopathy or arrhythmias
40% of patients with AL died of cardiac disease
biopsy and congo red staining of kidney, rectum or gingiva, or abdominal fat aspirates 75% of patients with generalized amyloidosis will be
positive
what tests should be performed in AL
-serum and urinary protein electrophoresis and immunoelectrophoresis should be performed
what will bone marrow aspirate show in AL patients
plasmacytosis
the prognosis of AA depends on what
on control of underlying condition
Myeloma-associated amyloidosis has poor prognosis but may respond to treatment of what
myeloma
