1
Q
How is complement activated in innate immunity?
A
-by microbes using the alternative or lectin pathways
2
Q
Follicular dendritic cells
A
- present in germinal centres
- have Fc receptors for IgG and receptors for C3b so can trap antigen bound to antibody of complement
- involved in antigen presentation to B cells in humoral immunity
3
Q
Roles of macrophages in immunity
A
- antigen presenting cells to T cells (activate T cells)
- activated by T cells to kill ingested microbes
- phagocytosis and destruction of microbes that are opsonized by IgG and C3b
4
Q
Class I MHC molecules
A
- expressed on all nucleated cells and platelets
- encoded by HLA-A, B and C
- display peptides derived from cytoplasmic proteins (e.g. viral antigens, tumor antigens) and present them to CD8 T cells
- the TCR recognizes the MHC-peptide complex and the CD8 molecule is a coreceptor that binds the Class I heavy chain
- CD8 cells are class I - MHC restricted
5
Q
Other genes encoding by the MHC locus
A
-complement components, TNF, lymphotoxin
6
Q
Role of cytokines in immune system
A
- messengers that mediate interactions and effector functions of leukocytes (i.e. interleukins)
- some cytokines (colony stimulating factors) stimulate hematopoiesis to increase leukocyte responses during inflammation and to replace leukocytes killed during immune responses
7
Q
Cytokines of innate immunity
A
- produced by macrophages, dendritic cells and NK cells
- produced rapidly and mediate inflammation and viral defense
- TNF, IL-1, IL-12, IFN-gamma
8
Q
Cytokines of adaptive immunity
A
- made by CD4 T cells
- promote lymphocyte proliferation and differentiation
- IL-2, IFN-gamma, other interleukins
9
Q
What is the clonal selection hypothesis?
A
-that lymphocytes specific for a large number of antigens exist before exposure to the antigen, and these get activated when antigen arrives
10
Q
What is affinity maturation?
A
- process of producing antibodies with high affinity for the target antigen
- isotype switching is induced by cytokines such as IFN-gamma and IL-4, and helper T cells also stimulate production of specific antibodies
11
Q
What is a hypersensitivity reaction?
A
-a pathologic reaction to an antigen that was previously encountered
12
Q
Features of hypersensitivity reactions
A
- can be against exogenous or endogenous (autoimmune) antigens
- development of these diseases is often associated with specific HLA types
- reflects an imbalance between the effector and control mechanisms of immune responses
13
Q
Features of type III (immune complex mediated) hypersensitivity
A
- antigen-antibody complexes are formed in the circulation and deposit in tissues (often kidney, joints), where they result in inflammation and tissue damage, often manifest as vasculitis/fibrinoid necrosis
- complement fixing antibodies (IgM and IgG) induce the pathologic lesions; complement is consumed in these reactions so the patient has hypocomplementemia
- examples: serum sickness, SLE, poststrep GN, polyarteritis nodosa
14
Q
Features of type IV (delayed type/cell mediated) hypersensitivity reactions
A
- initiated by antigen-sensitized T cells, usually CD4 but also CD8
- upon repeat exposure to antigen, previously sensitized Th1 cells respond and secrete IFN-gamma and other cytokines that actiate macrophages that phagocytize and kill organisms
- the activated macrophages express more MHC class II on their surface, promoting further antigen presentation, secrete cytokines that produce inflammation, and produce IL-12 which amplifies the Th1 response
- Th17 cells secrete cytokines that recruit neutrophils and monocytes
- morphologically characterized by CD4 cells and macrophages that cuff around vascular structures
- with pesistent antigens, over 2-3 weeks macrophages dominate and form granulomas
- examples: DM1 (probably via CD8 mechanisms), MS, RA, Crohn’s disease, contact dermatitis
15
Q
Define central tolerance
A
- immature self-reactive T and B cells are killed or inactivated during maturation
- immature lymphocytes that encounter the antigens for their TCR in the thymus die by apoptosis (negative selection)
- AIRE (autoimmune regulator) stimulates expression of “peripheral restricted” self antigens in the thymus and is required for deletion of self-reactive T cells
- developing B cells in the bone marrow that recognize self antigens undergo antigen receptor gene rearrangement so they no longer recognize self (receptor editing)
16
Q
Define peripheral tolerance
A
- anergy: prolonged/irreversible functional inactivation of lymphocytes induced by encountering antigens under certain conditions, such as when antigen is presented by cells that lack costimulators
- suppression by regulatory T cells (cells produced in the thymus that express CD25 and Foxp3
- deletion by activation-induced cell death: CD4 cells recognizing self-antigens may express a pro-apoptotic member of the Bcl family and die by apoptosis
17
Q
Define epitope spreading
A
- infections and/or an autoimmune reaction damage tissue and may release self-antigens and expose epitopes of the antigens that are normally concealed from the immune system, resulting in continuing activation of lymphocytes that recognize these epitopes (which were normally not exposed to the immune system and therefore there was no tolerance for them)
- a possible cause for the progression/persistence of autoimmune diseases
18
Q
4 patterns of ANA fluorescence and their significance
A
- homogenous/diffuse nuclear staining: antibodies to chromatin, histones or dsDNA
- rim/peripheral: dsDNA
- speckled: common and non-specific
- nucleolar: systemic sclerosis
19
Q
Which autoantibodies are most specific for SLE?
A
-anti-dsDNA and anti-Sm
20
Q
Factors involved in the pathogenesis of SLE
A
- genetic (e.g. certain HLA types, complement mutations, familial association)
- immunologic factors
- environmental factors
21
Q
What creates the “wire loop” lesion in lupus nephritis?
A
-subendothelial deposits that homogenously thicken the capillary wall
22
Q
Skin immunofluorescence findings in SLE
A
-Ig and C3 deposits along dermoepidermal junction, including in non-involved skin (in systemic lupus only)
23
Q
What is Libman-Sacks endocarditis?
A
- verrucous nonbacterial endocarditis seen in lupus
- deposits may be single or multiple, 1-3 mm, and are characteristically deposited on both sides of the leaflet of any valve
24
Q
Most common causes of death in SLE?
A
- renal filure
- intercurrent infection
- coronary artery disease (becoming more important)
25
Nature of the infiltrate in Sjogren's syndrome
-mostly CD4 cells with some admixed B cells including plasma cells
26
What is Mikulicz syndrome?
-refers to the combination of lacrimal and salivary gland enlargement from any cause (not just Sjogren's), such as sarcoid, lymphoma, etc
27
What antibody is specific for systemic sclerosis?
Anti-DNA topoisomerase I (anti-Scl70)
| Also anticentromeric antibody (found more often in those with CREST or limited cutaneous syndromes)
28
Characteristic vascular changes in skin in systemic sclerosis?
-intimal proliferation of digital arteries
29
Main features of scleroderma
- fibrosis of skin and other organs
| - vascular changes
30
Autoantibody in mixed connective tissue disease?
-anti-ribonucleoprotein particle containing U` ribonucleoprotein
31
Features of Bruton (X-linked) a gammaglobulinemia
- defect in maturation of B cells such that mature B cells nad plasma cells are absent but pre-B cells (CD19+ are present in the bone marrow)
- susceptible to bacterial infections as well as giardia and some viral infections
- caused by mutation in Bruton tyrosine kinase on X chromosome
- manifest symptoms around 6 months after depletion of maternal immunoglobulins
- treated by Ig replacement
- mostly males
- poorly developed B cell zones of lymphoid tissues
32
Features of CVID
- defects in plasma cell differentiation
- normal B cell numbers but no plasma cells
- recurrent sinopulmonary infections
- both sexes affected equally; later onset than X-linked hypogammaglobulinemia
- increased risk of lymphoid malignancies
33
DiGeorge syndrome
- deletion at 22q11 that results in failure to develop the 3rd and 4th pharyngeal pouches
- T cell deficiency (viral and fungal infection) due to thymic hypoplasia, tetany from lack of parathyroids and congenital cardiac defects
34
Examples of other primary immunodeficiencies
- isolated IgA deficiency:decreased mucosal defenses
- hyper IgM syndrome: lots of IgM but defective production of other Igs resulting in recurrent pyogenic infections
- Wiskott-Aldrich syndrome: X-linked (WASP gene) with eczema, thrombocytopenia and secondary depletion of T cells
- SCID: several types (X-linked, autosomal recessive) with defects in both humoral and cell-mediated immunity; candida, failiure to thrive, recurrent infections
- complement deficiencies: many cause non-infection related complications such as autoimmunity, paroxysmal nocturnal hemoglobinuria, hereditary angioedema
35
4 stages in HIV life cycle
1. infection of cells
2. integration of provirus into host genome
3. activation of viral replication
4. release of infectious virus
36
Lymph node findings in HIV
- marked follicular hyperplasia with depletion of the mantle zones, resulting in the appearance of follicles merging with the interfollicular areas
- in late stages there is disruption of the follicular dendritic network and sometimes hyalinization of germinal centres
37
Define amyloid
-a pathologic proteinaceous substance that is deposited in the extracellular space in many tissues in a variety of clinical settings
38
Describe amyloid
- nonbranching fibrils, 7-10 nm in diameter
- beta-pleated sheet by xray crysallography, which is responsible for the birefringence
- 95% is composed of fibril proteins, 5% of P component and other glycoproteins
39
3 most common forms of amyloid
1. AL: usually lambda light chains, occasionally kappa; produced from free light chains secreted by monoclonal plasma cells (associated with plasma cell tumors; most common form)
2. AA: derived from serum amyloid-associated protien that is produced as part of the inflammatory acute phase response (associated with inflammation; secondary amyloidosis)
3. Abeta: core of AD plaques and deposits in BVs in Alzheimer's; protein is derived from amyloid precursor protein
40
Other types of amyloid
- transthyretin: seen in familial amyloid polyneuropathy and senile cardiac amyloidosis
- beta2 microglobulin: seen in long-term hemodialysis-associated amyloidosis
- prion proteins in prion diseases may acquire the staining and structural characteristics of amyloid
41
What are three categories of cytokines?
- cytokines of innate immunity, made by Brits, nk cells and macrophages
- cytokines of adaptive immunity, made by cd4 cells which promote lymphocyte proliferation
- cytokines that stimulate hematopoiesis, csf s
42
What are the mechanisms for self tolerance in the thymus and bone marrow?
Thymus: negative selection: apoptosis of cells that encounter self antigens in thymus
Bone marrow: receptor editing: receptor rearrangement of cells recognizing self antigen
Robbins first 10 chapters
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