Multi-System Autoimmune Disease Flashcards
What is the sequence of events in autoimmunity?
Initiating event + genetic susceptibility Breakdown of self-tolerance Auto-reactivity Humoral +/- cellular Autoimmune disease
What is involved in the susceptibility for the development of autoimmune disease?
Multifactorial
Involves interaction of internal factors e.g. genes, hormones, immune dysregulation with exogenous factors e.g. infections, drugs, UV radiation
When combined together, the initiating exogenous factors in an inherently susceptible individual leads to a breakdown of damaging immune response and ultimately tissue or organ damage
- genetic/regulatory/hormonal/environmental/other factors
- breakdown of immunological tolerance
- pathological autorecognition
- inflammation and tissue damage, autoimmunity, hypersensitivity
Autoimmune diseases are conventionally organised into what?
Those which are predominantly organ specific i.e. where the aberrant immune response is directed against self-antigens which are localised or confined to particular tissues
Non-organ specific i.e. where the immune response is directed against self-antigens which have a more widespread, ubiquitous distribution
Some diseases in the middle of the spectrum tend to have a mixture of both organ-specific and non-organ specific immunopathology
The connective tissue disorders are all at the non-organ specific pole of the spectrum
What is involved in immune pathology?
Autoimmunity
Hypersensitivity
Immune deficiency
What are the functions of the complement system?
Phagocyte chemotaxis
Opsonisation
Lysis of micro-organisms
Maintaining solubility of immune complexes
The complement system is a component of what immune system?
Innate
What does the complement system comprise?
Collection of serum proteins organised into a classical pathway, an alternate pathway and a terminal pathway
Control of proteins in the serum and body fluids which prevents inappropriate complement activation, or down regulate and turn off complement activation
Series of cell surface control proteins which control and regulate the activity of the complement pathway
What is the classical pathway activated by?
Immune complexes containing IgG and IgM
Antigen bound IgM is particularly effective at classical pathway activation
The alternate pathway cycles constantly at what rate?
Very low rate of physiological activity
What is the alternate pathway up-regulated by?
A number of factors, including exposure to endotoxin-producing micro-organisms
At what point do the classical and alternate pathways converge?
At the point of breakdown of C3 into its breakdown products C3a and C3b
What happens in the terminal pathway?
C5 is broken down into C5a and C5b and the components C6, C7, C8 and C9 sequentially bind to C5b to form a multi-molecular C5b-C6-C7-C8-C9 complex called the membrane attack complex
In what diseases are the opsonisation function and maintenance of immune complex solubility of focal importance?
Connective tissue disease, particularly those where abnormal production, handling and deposition of immune complexes are involved in disease pathogenesis
Employment of complement measurements has three principle areas of importance in connective tissue disease, what are these?
Diagnosis
Monitoring
Detection of hereditary deficiencies
What do complement components roughly reflect?
The amount of immune complexes being generated, the more immune complexes being produced during disease exacerbation the more complement is consumed and the lower the measured levels
What happens to complement as diseases go into remission?
Immune complex production decreases and complement levels rise
Measuring complement levels can therefore be useful in disease diagnosis and in the monitoring of disease activity
In what disease is complement measurement of little practical value?
In diseases such as RA which are caused mainly by cellular mechanisms with only a small pathogenic component of localised immune complex formation
The use of complement tests for consideration and detection of hereditary complement deficiencies is principally a reflection of what?
The important role of classical pathway components (C1, 2 and 4) and their breakdown products in opsonisation and maintaining the solubility of immune complexes, and in preventing their pathological deposition into tissues
What happens when there are genetic deficiencies of one or more classical pathway component?
Immune complexes being produced in the course of a normal reaction to infection/dietary proteins etc. cannot be dealt with by normal pathological mechanisms and so readily deposit out of solution into tissues e.g. kidneys, joints and skin
Damage is therefore not the result of inappropriate and excessive immune complex formation but rather an inability to handle and dispose of even normal levels of immune complex formation
In classical pathway deficiencies, what is a major clue that the mechanistic problem lies within the complement system rather than ANA autoantibody production?
Patients are ANA negative
What are the features of complement deficiency?
Genetic deficiencies of components in three main parts of the complement system, presenting in characteristic but different ways
Alternate and terminal pathways present with infection
Deficiencies of classical pathway components characteristically present as lupus-like systemic immune complex disease
What are cryoglobulins?
Immunoglobulin molecules which reversibly precipitate out of solution at temperatures under 37 degrees celsius
In what conditions are cryoglobulins seen?
Livedo reticularis Raynaud's Peripheral cyanosis Purpura/vasculitis Glomerulonephritis Neuropathy Arthralgia Thrombosis Haemorrhage
How are connective tissue diseases diagnosed?
History
Examination
Relevant investigations
Laboratory investigations
What are the performance characteristics?
Accuracy Precision Sensitivity Specificity \+ve/-ve predictive value Purpose for which the test is used
What are the test purposes in relation to disease?
Diagnosis Sub-Classification Prognosis/risk stratification Monitoring/progression Screening Research
What are the test purposes in relation to treatment?
Planning Selection Triage Monitoring Evaluation
What are the things to consider when ordering a test?
Why you are ordering it
What the consequences of doing/not doing the test are
How good the test is for the purpose for which you are using it
How the results are interpreted
How the results will influence patient management and outcome
What are the immunology tests?
Antinuclear antibodies Antineutrophil cytoplasmic antibodies Antiphospholipid antibodies Complement Cryoglobulin Rheumatoid factor Anti-CCP Serum immunoglobulin Autoantibodies against formed elements in the blood Tissue typing Biopsy of skin or kidney s
Why might immunological tests be useful?
Diagnosis
Prognostic assesemnet
Monitoring
of connective tissue diseases
Why might autoantibodies be of use?
Disease diagnosis
Monitoring of disease activity
Sub-classification of disease
What is the sensitivity to antinuclear antibody testing in; SLE Drug-induced LE MCTD RA Sjogren's Scleroderma Dermatomyositis Old age Chronic inflammation Neoplasia CAH PBC Normality
SLE > 95% Drug-induced LE 95% MCTD 95% RA 50% Sjogren's 60% Scleroderma 60% Dermatomyositis 15% Old age > 40% Chronic inflammation > 30% Neoplasia 10% CAH 70% PBC 25% Normality 3-5%
What are the features of SLE?
Systemic autoimmune disorder mediated by widespread deposition of immune complexes (type III hypersensitivity) containing autoantigen and autoantibody throughout the body
Deposits happen throughout body but have a predilection for the skin, joints and kidney
Autoantibodies characteristically produced against a range of nuclear auto antigens but also against a range of other non-organ specific autoantigens e.g. cardiolipin and ribosomes
ANA has a high sensitivity but very low specificity for SLE, what does this mean?
It has high negative predictive value and low positive predictive value
If ANA test -ve, SLE is extremely unlikely
Almost all cases of SLE will have detectable ANA but in the general population, an ANA test done for non-specific symptoms with a positive result is unlikely in itself to be indicative of SLE, why is this?
As SLE is relatively rare and other conditions e.g. cancer, old age and infection can cause a positive ANA and are more common
Why is ANA testing more useful to exclude SLE in a patient with non-specific symptoms?
Because of the high predictive value of a negative result
What are the four different patterns of ANA staining seen using the fluorescent test?
Homogenous pattern staining - present when there are autoantibodies directed against chromosomal autoantigens (double/single stranded or histone proteins)
Speckled pattern staining - where there are autoantibodies directed against non-chromosomal nuclear proteins (which are physically distinct from nucleic acids in the nucleus)
Nucleolar staining - where autoantibodies are directed solely against nucleolar RNA
Peripheral/membranous staining - where staining is confined to the nuclear membrane
What potential autoantigens are contained in the human nucleus?
Double stranded DNA Single stranded DNA Histone proteins Nucleolus Non-histone nuclear proteins
In some conditions, particularly in SLE, autoantibodies can be produced against a range of nuclear autoantigens, what does this result in?
Different staining patterns on testing when visualised down a microscope
In homogeneous staining, in what conditions are dsDNA, ssDNA and histone proteins seen?
dsDNA - SLE, some autoimmune liver disease
ssDNA - non-specific, many inflammatory disorders
Histone proteins - drug-induced lupus, other connective tissue disorders
