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How is complement activated in innate immunity?

-by microbes using the alternative or lectin pathways


Follicular dendritic cells

-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


Roles of macrophages in immunity

-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


Class I MHC molecules

-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


Other genes encoding by the MHC locus

-complement components, TNF, lymphotoxin


Role of cytokines in immune system

-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


Cytokines of innate immunity

-produced by macrophages, dendritic cells and NK cells
-produced rapidly and mediate inflammation and viral defense
-TNF, IL-1, IL-12, IFN-gamma


Cytokines of adaptive immunity

-made by CD4 T cells
-promote lymphocyte proliferation and differentiation
-IL-2, IFN-gamma, other interleukins


What is the clonal selection hypothesis?

-that lymphocytes specific for a large number of antigens exist before exposure to the antigen, and these get activated when antigen arrives


What is affinity maturation?

-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


What is a hypersensitivity reaction?

-a pathologic reaction to an antigen that was previously encountered


Features of hypersensitivity reactions

-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


Features of type III (immune complex mediated) hypersensitivity

-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


Features of type IV (delayed type/cell mediated) hypersensitivity reactions

-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


Define central tolerance

-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)


Define peripheral tolerance

-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


Define epitope spreading

-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


4 patterns of ANA fluorescence and their significance

-homogenous/diffuse nuclear staining: antibodies to chromatin, histones or dsDNA
-rim/peripheral: dsDNA
-speckled: common and non-specific
-nucleolar: systemic sclerosis


Which autoantibodies are most specific for SLE?

-anti-dsDNA and anti-Sm


Factors involved in the pathogenesis of SLE

-genetic (e.g. certain HLA types, complement mutations, familial association)
-immunologic factors
-environmental factors


What creates the "wire loop" lesion in lupus nephritis?

-subendothelial deposits that homogenously thicken the capillary wall


Skin immunofluorescence findings in SLE

-Ig and C3 deposits along dermoepidermal junction, including in non-involved skin (in systemic lupus only)


What is Libman-Sacks endocarditis?

-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


Most common causes of death in SLE?

-renal filure
-intercurrent infection
-coronary artery disease (becoming more important)


Nature of the infiltrate in Sjogren's syndrome

-mostly CD4 cells with some admixed B cells including plasma cells


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


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)


Characteristic vascular changes in skin in systemic sclerosis?

-intimal proliferation of digital arteries


Main features of scleroderma

-fibrosis of skin and other organs
-vascular changes


Autoantibody in mixed connective tissue disease?

-anti-ribonucleoprotein particle containing U` ribonucleoprotein