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immunopathy IV Flashcards

1
Q

pathogenesis of Rheumatoid arthritis (RA)

A
  • Unknown antigenic trigger leads to initiation of synovitis
  • ongoing autoimmune reaction is mediated by activated CD4+ T cells which produce cytokines and activate B cells
  • -> Cytokines activate macrophages, lymphocytes, neutrophils in join space –> release of degradative enzymes and inflammation
  • -> IL-1 cause proliferation of synovial cells and fibroblast
  • -> TNF causes leukocyte recruitment
  • -> activated B cells produce IgM auto-Ab to attack Fc portion of autologous IgG called Rheumatoid factor (RF)
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2
Q

describe morphology of RA

A
  • Nonsupportive, proliferative, DESTRUCTIVE synovitis
  • Edema, synovial cell hyperplasia, stromal and perivascular infiltrates
  • Fibrin deposition on synovial surface and exudation into joint space
  • pannus formation = granulation tissue, synovial and inflammatory cells, fibrous CT
  • Articular cartilage erosion, osteoclastic DESTRUCTION of subchondral bone –> ankylosis (consolidation and immobility)
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3
Q

describe the X-ray of RA

A
  • diffuse osteopenia (loss of joint space)
  • marked loss of joint spaces of the carpal, metacarpal and interphalangeal joints
  • ulnar drift of the fingers
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4
Q

describe extra-articular lesions of RA

A
  • rheumatoid nodules in 25% of cases
  • -> skin at pressure points: elbow, occiput, lumbosacrum
  • -> viscera at lungs, spleen, heart
  • Small vessel vasculitis especially in cases of severe disease with high titers of RF
  • -> (RF-IgG complexes –> type III damage)
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5
Q

describe the clinical course of RA

A
  • variable = mild discomfort –> progressive diability
  • features = malaise, fatigue, pain, swelling, stiffness, deformity of small and large joints
  • COD
  • -> disease complications of amyloidosis, vasculitis
  • -> drug therapy complications of bleeding, infection
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6
Q

describe Juvenile varient of RA: juvenile idiopathic arthritis

A

-

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7
Q

describe Mixed connective Tissue disease (MCTD)

A
  • Clinical syndrome with overlapping features of SLE and systemic Sclerosis
  • specific Ab (anti-U1RNP) to ribonucleoprotein
  • clinically distinctive because of minimal renal disease and GOOD RESPONSE to STEROID therapy
  • may evolve into classic SLE or SS with resultant severe renal disease and pulmonary hypertension
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8
Q

describe primary immunodeficiencies

A
  • generally rare, genetically determined defects of B and T lymphocytes
  • combined or overlap defects due to common stem cell and regulatory role of helper T cells
  • Clinical manifestations
  • -> repeated infection, failure to thrive, 6months to 2 years
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9
Q

Describe X-Linked Agammaglobulinemia of bruton

A
  • X-linked recessive transmission affecting MALE infants
  • Due to Genetic mutation of B cell TYROSINE KINASE gene (btk gene) –> plays a critical role in pre-B cell signalling
  • Defect = failure of maturation of pro-B and pre-B cells into B cells, and terminal differentiation into antibody producing plasma cells
  • normal pre-B cell population; lack of further differentiation –> absence of mature B cells in blood, peripheral lymphoid tissue
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10
Q

Describe the clinical course of X-linked Agammaglobulinemia of bruton

A
  • appear after depletion of maternal Ab
  • recurrent sinus, oropharyngeal and respiratory infections due to PYOGENIC BACTERIA (staph, strep, influenza etc; organisms usually opsonized by Ab and cleared by phagocytosis)
  • may be viewed as a disorder of opsonization
  • Cellular immunity intact but lack of IgA antibodies needed for neutralization of circulating an mucosal viruses and for mucosal defense
  • Increased frequency of autoimmune disorders
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11
Q

describe common variable immunodeficiency

A
  • heterogeneous group of disorders with sporadic and inherited forms
  • Main feature = hypogammaglobulinemia (low amounts of Ig), usually all AB classes, but occasionally isolates IgG
  • variable mechanisms
  • -> intrinsic B cell defect (differentiation)
  • -> abnormal T cells ignaling to B cells (increase suppressor or decrease helper activity)
  • inability of B cells to develop into plasma cells
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12
Q

Describe the clinical course of X-linked Agammaglobulinemia of bruton

A
  • appear after depletion of maternal Ab
  • recurrent sinus, oropharyngeal and respiratory infections due to PYOGENIC BACTERIA (staph, strep, influenza etc; organisms usually opsonized by Ab and cleared by phagocytosis)
  • may be viewed as a disorder of opsonization
  • Cellular immunity intact butr lack of IgA antibodies needed for neutralization of circulating an mucosal viruses and for mucosal defense
  • Increased frequency of autoimmune disorders
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13
Q

describe Selective IgA deficiency

A
  • MOST COMMON, mild
  • familial or acquired in association with measles, toxoplasmosis infections
  • Serum/secretory IgA absent or Decreased because IgA + B cells FAIL TO MATURE
  • Cellular immunity intact
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14
Q

describe common variable immunodeficiency

A
  • heterogeneous group of disorders with sporadic and inherited forms
  • Main feature = hypogammaglobulinemia, usually all AB calsses, but occasionally isolates IgG
  • variable mechanisms
  • -> intrinsic B cell defect (differentiation)
  • -> abnormal T cells ignaling to B cells (increase suppressor or decrease helper activity)
  • inability of B cells to develop into plasma cells
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15
Q

describe the clinical features of common variable immunodeficiency

A
  • recurrent bacterial infections of sinuses and respiratory tract
  • lack of IgA causes Increase enterociral infections and chronic diarrhea due to unrelenting Giardia lamblia infection
  • paradoxical increase incidence of Al disorder (RA)
  • Increase risk of lymphoid cancers and increase gastric cancers seen
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16
Q

describe the clinical features of common variable immunodeficiency

A
  • recurrent bacterial infections of sinuses and respiratory tract
  • lack of IgA causes Increase enterociral infections and chronic diarrhea due to unrelenting Giardia lamblia infection
  • paradoxical increase incidence of Al disorder (RA)
  • Increase risk of lymphoid cancers and increase gastric cancers
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17
Q

describe Selective IgA deficiency

A
  • MOST COMMON, mild
  • familial or acquired in association with measles, toxoplasmosis infections
  • Serum/secretory IgA absent or Decreased becaue IgA + B cells fail to mature
  • CEllular immunity intact
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18
Q

describe Selective IgA deficiency

A
  • MOST COMMON, mild
  • familial or acquired in association with measles, toxoplasmosis infections
  • Serum/secretory IgA absent or Decreased becaue IgA + B cells fail to mature
  • CEllular immunity intact
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19
Q

describe the clinical features of Selective IgA deficiency

A
  • Asymptomatic or recurrent GI, respiratory, GU infections secondary to weakend mucosal defenses
  • 40% may have anti-IgA Ab leading to anaphylactic reaction if transfused blood containing IgA or given IV immunoglobulin therapy
  • Increased tendency to develop AI disorders (SLE, RA)
20
Q

describe Hyper IgM syndrome

A
  • Characterized by FAILURE OF T CELLS TO:
  • -> induce B cell isotype switching from IgM to IgG, IgA and IgE
  • -> activate macrophages to remove intracellular microbes
  • IgM producing B cells normally activate transcription genes that encode for other Ig isotypes via signals between CD 40 molecules on B cells and CD40 ligand on helper T cells
  • IgM is normal or Increased; other isotypes absent; IgG decreased or absent
  • Normal B and T cell populations
21
Q

Describe the transmission of Hyper IgM syndrome

A
  • X-linked pattern
  • autosomal recessive pattern
  • -> mutation of gene for CD40
  • -> mutation of activation induced deaminase (AID) enzyme required for class switching
22
Q

describe the clinical course of Hyper IgM syndrome

A
  • lack of opsonizing IgG leads to recurrent pyogenic infections
  • lack of phagocytic activation leads to infection by intracellular organisms
  • IgM reactions against blood cells leads to autoimmune lysis
  • GIT lympoid hyperplastic accumulations of IgM+ B cells
23
Q

describe DiGeorge syndrome

A
  • partial or complete interruption of 3rd and 4th pharyngeal pouch development LEADS TO Aplasia or hypoplasia of thymus (T cell development) and parathyroids; also abnormalities of face and aortic arch
  • Features = T cell defect, HYPOCALCEMIA, cardiac anormalities, cleft palate
  • CHROMOSOME 22q11 DELETION
24
Q

what are the clincial features of DiGeorge syndrome

A
  • viral and fungal infectiosn common
  • dysmorphology:
  • -> facial = low set ears, midline clefts, small mandible
  • -> cardiac = VSD, right subclavian artery derived from pulmonary arch
  • Cardiac anomalies lead to perinatal death
  • Hypoplasia = immune defect resolves by age 5
  • Aplasia = requires transplantation of fetal thymus
25
Q

describe the genetics of Severe combined immunodeficiency disease (SCID): X-link pattern

A
  • X-linked pattern causes mutation of common gamma-chain subunit of cytokine receptors
  • -> affects interleukin which IMPAIRES lymphocyte development, proliferation and function
26
Q

describe the genetics of Severe combined immunodeficiency disease (SCID): Autosomal recessive pattern

A
  • Adensoine deaminase (ADA) deficiency leads to lymphoTOXIC metabolites (deoxyadensoine, deoxy-ATP)
  • Failures of Class II MHC expression causes IMPAIRED T cell recognition of Ag
27
Q

describe the clincial features of SCID

A
  • very severe (think bubble boy)
  • early onset = 3 months with thrush, diaper rash, failure to thrive
  • recurrent infections from all microbes: bacteria, viruses, fungi, protozoa
  • therapy = bone marrow transplantation; gene therapy for ADA and more recently gamma-chain mutation using adenoviral or retroviral vectors
28
Q

describe Wiskott-aldrich syndrome

A
  • X-linked disorders of male infants
  • Features = immunodeficiency, thrombocytopenia and eczema (erythematous scaly rash)
  • Defect in W-A syndrome protein gene responsible for CYTOSKELETAL MAINTENANCE and LINKAGE OF MEMBRANE RECEPTORS TO CYTOSKELETION causes progressive depletion of T and B cells
29
Q

what are the results of wiskott-aldrich syndrome

A
  • Ab levels normal (IgG) or elevated (IgA, IgE) with eception of IgM which is low
  • no Ab to polysaccharide Ag, poor Ab response to protein Ag (Ab DON’T FUNCTION PROPERLY)
  • T cell deficit secondary progressive, peripheral depletion in blood and nodal tissue
30
Q

what are the clinical features of Wiskott-aldrich syndrome

A
  • hemorrhagic diathesis
  • recurrent respiratory infections
  • pyogenic bacteria, viruses, fungi
  • early death without bone marrow transplant
  • if they survive… INCREASE lymphoid malignancies in survivors past age 10
31
Q

what causes impaired immunity

A
  • extremes of age
  • metabolic states
  • drugs
  • infiltrative and hematologic disorders
  • burns, trauma, chronic infection (EBV)
32
Q

describe Acquired immunodeficiency syndrome

A
  • HIV-1 retroviral infection
  • targets immune system and CNS
  • immunosuppression
  • opportunisitc infection
  • rare neoplasms
  • neurologic abnormalities
33
Q

what are the risk groups for AIDS

A
  • homosexual/bisexual males
  • intravenous, subcutaneous drug users
  • recipients of transfused blood, blood products
  • heterosexual contacts
34
Q

describe the effects of AIDS

A
  • selective lymphopenia of CD4+ T cells with diminished T cell function
  • polyclonal B cell activation with hypergammaglobulinemia yet impaired specific B cell response to new Ag
  • altered macrophage function with DECREASED MHC II expression and Ag presentation
35
Q

describe the natural history of AIDS: early and middle

A
  • early, acute phase
  • -> viral replication, viremia, viral seeding of lympoid tissue
  • -> fever, sore throat, myalgias
  • Middle, chronic phase:
  • -> replication in lymphoid tissue persists
  • -> lymphadenopathy, weight loss, night sweats, fatigue, fever +- rash
36
Q

describe the natural history of AIDS: final phase

A
  • final, crisis phase:
  • -> marked viral replication
  • -> depletion of T cells leads to profound immune suppression
  • -> fever, fatigue, weight loss
  • -> opportunistic disease, neoplasms
37
Q

describe the Pathogenesis of AIDS: BINDING

A
  • HI envelop surface glycoprotein (gp) 120 binds to CD4+ molecules on target cells
  • -> requires assistance of chemokine co-receptors CCR5 and CXCR4
38
Q

describe the pathogenesis of AIDS: FUSION

A
  • HIV envelop transmembrane gp 41 inserts into the target cell membrane causing fusion of viral envelop with cell membrane and internalization of virus
39
Q

describe the pathogenesis of AIDS: DNA synthesis

A
  • once internalized, viral RNA genome is transcribed to DNA copy (cDNA or proviral DNA) by REVERSE TRANSCRIPTASE ENZYME
40
Q

describe the pathogenesis of AIDS: Integration

A
  • in quiescent cells, cDNA may remain latent in cytoplasm

- in dividing cells, cDNA is integrated in the host genome via the viral enzyme INTEGRASE

41
Q

describe the pathogenesis of AIDS: REplication

A
  • cDNA may be transcribed to form complete viral particles that bud from the cell membrane thereby killing the host cell or the infected cell may be activated, possibly by infection or cytokines resulting in production viral peptide chains
  • -> HIV protease enzyme cleaves functional viral proteins from the polypeptide chain for assembly of complete virion
42
Q

describe the pathogenesis of AIDS: dissemination

A

viral release by budding from cell surface or lysis of cell

43
Q

describe the pathogenesis of AIDS: dissemination

A

viral release by budding from cell surface or lysis of cell

44
Q

Describe the mechanisms of T cell loss in AIDS ***

A
  • Viral replication in infected CD4+ T cells leads to death of infected cells (cytopathic effect of virus
  • Activation of uninfected CD4+ T cells leads to activation-induced cell death (apoptosis)
  • expression of HIV peptides on infected CD4+ T cells leads to killing of infected cells by virus-specific CTLs
45
Q

Describe the mechanisms of T cell loss in AIDS ***

A
  • Viral replication in infected CD4+ T cells leads to death of infected cells (cytopathic effect of virus
  • Activation of uninfected CD4+ T cells leads to activation-induced cell death (apoptosis)
  • expression of HIV peptides on infected CD4+ T cells leads to killing of infected cells by virus-specific CTLs
46
Q

describe the mechanisms of HIV infection in developing Lymphomas

A

Early infection:
- Increased follicular T helper cells cause germinal center B cell hyperplasia which results in B cell lymphomas with translocations (burkitt lymphoma and large B cell lymphoma)
Advanced infection:
- T cell depletion leads to unchecked EBC/KSHV reactivation in latently infected B cells which results in virus-associated B cell lymphomas

47
Q

describe the mechanisms of HIV infection in developing Lymphomas*

A

Early infection:
- Increased follicular T helper cells cause germinal center B cell hyperplasia which results in B cell lymphomas with translocations (burkitt lymphoma and large B cell lymphoma)
Advanced infection:
- T cell depletion leads to unchecked EBV/KSHV reactivation in latently infected B cells which results in virus-associated B cell lymphomas (EBV etc)

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