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Immunology and Immunological Disorders > Auto-immune Diseases > Flashcards

Auto-immune Diseases Flashcards

1
Q

Auto-immunity

A

Immune response of auto-Ab against self-Ab. Humoral or cell-mediated immune response against the components of the own cell/tissue.

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2
Q

Auto-antibody and auto- or self-antigens

A
  • Auto- antibody: Altered cell (Auto Ag) elicits the production of antibody
  • Auto or self-antigens: Antigens present in one’s own cells which are altered by the action of bacteria, viruses, chemicals or drugs
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3
Q

Auto-immune diseases

A

Is a group of disorders in which tissues injury is caused by humoral (by auto-antibodies) or cell-mediated immune response (by auto-reactive T-cells) to self antigens. Normally, the immune system does not attack the self. However, there is a large group of auto-immune diseases in which the immune system does not attack self cells. The attack can be directed either against a very specific tissue, or to a large number of tissues. Auto-immune diseases can be difficult to treat.

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4
Q

Types of immune response involved

A

Adaptive immune response involved
- Highly-specific pathogen-mediated process
- B-cells (humoral immunity) and T-cells (cellular immunity)
- Distinguish between self and non-self
- Develop immune repertoire (immunological memory)

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5
Q

Causes of autoimmune diseases

A
  1. Sequestered or hidden antigens
    - Ag in the secluded places are not accessible to the immune system
  2. Neo antigens
    - Altered/modified antigens - by physical (irradiation), chemical (drugs), or microbial agents (intracellular viruses)
  3. Molecular mimicry
    - A foreign antigen resembles self
    - Many species share organ specific antigens
  4. Loss of immunoregulation
    - Loss of self-tolerance - cause by over activity or lowered activity of B- and T-cells
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6
Q

Prevalence of autoimmune diseases

A
  • Thyroid diseases (includes Hashimoto’s thyroiditis and Grave’s disease): >3% adult women
  • Rheumatoid arthritis: 1% of general population, but female excess
  • Primary Sjorgen syndrome: 0.6 - 3% of adult women
  • Systemic lupus erythematosus: 0.12% of general population but female excess
  • Type 1 diabetes: 0.1% of children
  • Primary biliary cirrhosis: 0.05-0.16% of middle aged and elderly women
  • Myasthenia gravis: 0.01% of general population but female excess
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7
Q

Examples of auto-immune diseases - organ specific diseases

A
  1. Type 1 diabetes - Pancreatic beta-cells
  2. Grave’s disease - Thyroid antigens and cell antigens
  3. Hashimoto thyroiditis - Thyroid proteins and cell antigens
  4. Vitiligo - Tyrosinase
  5. Pemphigus vulgaris - Desmoglein
  6. Myasthenia gravis - Acetylcholine receptor
  7. Lambert-Eaton syndrome - Voltage-gated Ca2+ channels
  8. Haemolytic anaemia - IgM/IgG binds to RBCs
  9. Thrombocytopenic purpura - Platelet glycoproteins
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8
Q

Endocrine

A

Endocrine glands contain specialised cells that are common targets for organ-specific autoimmunity because they express tissue-specific proteins and have a very good blood supply

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9
Q

Type 1 Diabetes

A
  • Selective destruction of insulin producing beta-cells in the pancreas:
  • Autoantibodies target insulin, glutamic acid decarboxylase and specific beta-cell proteins
  • CD8+ T-cells mediate cell destruction
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10
Q

Grave’s Disease

A

Grave’s disease is a common cause of hyperthyroidism, an over-production of the thyroid hormone, which causes an enlargement of the thyroid and other such symptoms such as exophthalamus, heat intolerance and anxiety.
- Bacterial viral trigger
- Abs to stimulating thyroid hormone receptor (TSHr)

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11
Q

Endocrine: pathology and therapy

A

Increased levels of:
- T3 (triiodothyronine)
- T4 (thyroxine)
- Persistent TSHr stimulation
Decreased levels of:
- TRH
- TSH
Treatment:
- Thyroidectomy
- Anti-thyroid drugs
- Radioiodine-131

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12
Q

Hashimoto’s thyroiditis: pathology and therapy

A
  • Hypothyroidism
  • Thyroid gland enlargement (goitive)
  • Reduced thyroid function (hypothyroidism)
  • Abs to thyroid oxidase (cytotoxicity)
  • Reduced metabolic rate
    Pathology and therapy
  • Increased levels of TSH
  • Decreased levels of T3 and T4
    Treatment
  • Replacement therapy
  • Natural desicated thyroid
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13
Q

Neurological: Myasthenia gravis

A
  • Skeletal muscle weakness - worsens with activity
  • Symptoms subside after periods of rest
  • Antibodies to the AChR and MuSK (muscle-specific kinase)
  • Facial muscles affected (speech/vision)
  • Destruction of neuromuscular connection (antibodies against nicotine recpetor)
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14
Q

Neurological: Lambert-Eaton syndrome

A
  • Antibodies to the voltage-gated Ca2+ channels
  • Decreases Ca2+ influx into nerve terminal
  • Proximal and distal muscle weakness
  • Ataxia
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15
Q

Pathology of LEMS

A

Normal depolirisation of the presynaptic nerve terminal by ion channels leads to an influx of calcium ions and subsequent release of ACh-containing vesicles; ACh binds to the ACh receptor, leading to depolarisation of the postsynaptic synapse and ultimately muscle contraction. In LEMS, VGCC antibodies block calcium influx, leading to reduced ACh vesicle release from the presynaptic membrane; therefore, reduced ACh is available to bind to the post-synaptic ACh receptors. Treatment with 3,4-diaminopyrimidine blocks the efflux of potassium ions prolonging the duration of depolarisation keeps the pathologically affected calcium channels open longer, increasing calcium ion influx and intracellular calcium concentration and thereby improving the ability of the ACh vesicles to fuse and release neurotransmitter

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16
Q

Haematological

A

Haemolytic Anaemia
- Organ specific autoimmune disorder in which IgG and IgM autoantibodies bind to RBCs and activate complement
- RBCs become spherocytic and phagocytosed by macrophages
- Symptoms of fatigue
Thrombocytopenic purpura
- Low platelet count
- Antibodies (IgG) to platelet surface glycoproteins
- Bleeding, bruising, rash (purpuric)
- Haematomas (mucous membrane)

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17
Q

Systemic Diseases

A

Features of auto-immune (AI) systemic diseases
- IgG auto-antibodies formed against cellular components can cause systemic auto-immune diseases
- Extracellular matrixproteins (collagen)
- Cell surface proteins (HLA antigens)
- Cytoplasmic proteins (actin, myelin)
- Nuclear components (histone, proteins DNA)
Systemic autoimmune diseases often involve periods of intense inflammation followed by periods of relative calm (remission)
- Lupus (SLE), multiple sclerosis, rheumatoid arthritis
Immune complexes (rheumatoid factors) form when IgM, IgG and IgA autoantibodies bind to the Fc regionof human IgG
- Immune complexes accumulate in many tissues

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18
Q

Diseases and autoantibody targets

A
  1. Poly/Dermatomyositis - Nuclear, DNA, tRNA, synthesases
  2. Rheumatoid arthritis - Citrullinated proteins and complexes
  3. Multiple sclerosis - Myelin sheath
  4. Systemic lupus erythmatosus (SLE) - DNA, nuclear and protein complexes
  5. Sjorgens syndrome - Nuclear protein and complexes
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19
Q

Dermatomyositis

A
  • Profound muscle weakness (symmetrical)
  • Rare: 6 - 7/100,000
  • Perifasicular atrophy (occurence of small muscle fibres at the periphery of a fascicle)
  • Proximal muscles
  • T-cell infiltration into muscles
  • Skin involvement
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20
Q

Rheumatoid Arthritis (RA)

A
  • Systemic autoimmune disorder that usually affects the joints, wrists, hands, elbows, shoulders, knees and ankles symmetrically
  • The synoviul membranes (synovium) of the joints become inflammed and produce excess fluid which accumulates in the joint
  • Cartilage becomes rough and pitted and bones often erode
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21
Q

Multiple Sclerosis (MS)

A
  • Destruction of the myelin sheath
  • Brain and spinal cord leisons
  • Sensory disturbances
  • Muscle control
  • Visual disturbance
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22
Q

Systemic Lupus Erythmatosus (SLE)

A
  • Plural effusions
  • Heart problems
  • Lupus nephritis
  • Arthritis
  • Butterfly rash
  • Raynaud’s phenomenon
  • Misdiagnosed (mimic)
  • Patients experience fatigue, ,muscle and joint pain and weakness
  • Unpredictable in nature
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23
Q

Sjorgens Syndrome

A
  • Dry mouth and eye (primary symptom)
  • Immune cells target glands
  • May impact multiple organ systems
  • Varied severity
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24
Q

Mechanisms

A
  • In healthy individuals, the immune system is tolerant of self-tissues
  • In auto-immune diseases, chronic and adaptive immune responses are directed towards normal body components.
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25
Q

Role of (self) antigens

A
  • Antigens are molecules or molecular fragments that can be bound by an MHC molecule and presented to a T-cell receptor
  • An auto-antigen is a self-antigen (an antigenic component/amino acid sequence) of the body that can provoke an immune response by the individuals own immune system
  • Inappropriate autoimmune responses to self-antigen can involve:
  • humoral mechanisms via B-cells and antibodies
  • cell-mediated mechanisms via T-cells and cytokines
26
Q

Function of T-cells

A
  • Diverse in function
  • Interaction with antigen often dictates fate
27
Q

Function of B-cells

A
  • Immunoglobulins on B-cell surface recognise and attach to antigen, which is then internalised and processed. Within the B-cell, a fragment of the antigen combines with HLA class II
  • HLA class-II antigen-fragment complex is displayed on B-cell surface
  • Receptor on the T-helper cell (Th cell) recognises complex of HLA class II antigen fragment and is activated - producing cytokines which activate the B-cell
  • B-cell is activated by cytokines and begins clonal expansion. Some of the progeny become antibody-producing plasma cells
28
Q

Clonal selection

A
29
Q

What is ‘tolerance’?

A

‘A state of indifference or non-reactivity towards a substance that would normally be expected to excite an immunological response’.
- The ability to ‘tolerate self-antigens’ results from exposure of self-antigens to autologous (self) lymphocytes in early development
- Tolerance is fundamental to the success of the immune system
- Failure to tolerate self antigens in the presence of other factors can trigger the development of an autoimmune disease

30
Q

Central tolerance

A
  • Regulation of B- and T-cells proliferating in the thymus and bone marrow
  • Renders them un-reactive to self-antigen
  • During early maturation, B- and T-cells are sensitive to self-antigen
  • Regulatory processes nullify this response
31
Q

Central tolerance - T-cells

A
  • T-cell receptor (TCR) gene rearrangement in immature T-cells randomly generate thousands of antigen-specific TCRs:
  • T-cells that express auto-reactive TCRs need to be eliminated
  • The thymus selects and eliminates auto-reactive T-cells:
  • It is very active in early life (located near the heart)
  • It positively selects T-cells with TCRs that bind to antigen-associated with MHC expressed by epithelial thymocytes
  • It negatively selects, and induces apoptosis in T-cells with high avidity (binding) for self-antigens on epithelial thymocytes
32
Q

Thymus

A

Thymocytes at different developmental stages are found in distinct parts of the thymus. The earliest cells to enter the thymus are found in the subcapsular region of the cortex. As these cells proliferate and mature into double-positive thymocytes, they migrate deeper into the thymic cortex. Finally, the medulla contains only mature single positive T-cells, which eventually leave the thymus and enter the bloodstream

32
Q

Central tolerance: T-cell activation

A
  • Autoimmune T-cells can be activated in a pathogenic-specific or a non-specific manner by infection:
  • Specific: specific pathogen antigens are presented to T-cells via T-cell receptor-MHC interactions
  • Non-specific: by inflammation or reduced regulation by cytokines
  • Inappropriate class II MHC expression activates B- or cytotoxic T-cells
  • Pacreatic B-cells express high levels of class II MHC in diabetes
  • Thyroid cells express high levels of class II MHC in Graeve’s Disease
  • Viruses promote interferon-gamma release by T-cells which can increase class II MHC expression by cells that should not express it
  • This may help induce an autoimmune disease following a viral infection
33
Q

Central tolerance: B-cells

A

Thousands of B-cell clones are randomly generated by gene rearrangements during foetal development, many will be auto-reactive and need eliminating by tolerance
- Developing B-cells undergo positive/negative selection in bone marrow, and germinal centres of other lymphoid tissues:
- Most autoreactive cells undergo apoptosis but some survive

34
Q

B-cell development and tolerance within the bone marrow

A

In both humans and mice, conventional B-cells begin their development in the bone marrow. Induction of RAG initiates VDJ recombination, which enables the developing B-cell to produce heavy and light chain immunoglobulin receptors and form a functional BCR. Immature B-cells are then subjected to central tolerance mechanisms that eradicate auto-reactive cells; B-cells that express BCRs that bind self-antigen expressed in the bone marrow undergo receptor editing in an attempt to produce BCRs that are not autoreactive. B-cells that successfully pass those central tolerance checkpoints leave the bone marrow and travel tothe spleen where they are subjected to further tolerance mechanisms

35
Q

Central tolerance: role of B-cells

A
  • When auto-reactive B-cells are stimulated by an auto-antigen, thy migrate to T-cell area of secondary lymphoid tissues:
  • If a T-cell is not available, the B-cells fail to thrive and die
  • If they recieve T-cell help, they may survive and cause disease
  • Some viruses (EBV) can induce non-specific polyclonal B-cell activation:
  • Activated B-cells can produce IgM which may combine with IgG to form immune antibody-antigen complexes
36
Q

Regulatory Elements - AIRE
Autoimmune Regulator (AIRE)

A
  • AIRE is a transcription factor
  • Localised to thymus (medulla)
  • Organ-specific proteins - peripheral tissues
  • Immunological self - shadow
  • Involved in negative selection
37
Q

AIRE

A

From transcriptional regulation to tolerance induction, AIRE promotes the ectopic transcriptional activity of a large number of chromosomal locations, thereby enhancing the expression by medullary epithelial cells (MEC’s) of genes that would normally only be expressed in specific tissues. This shadow of the peripheral self in MECs is then presented to immature thymocytes, either directly by the MECs themeslves or indirectly by uptake of antigens released from MECs by thymic dendritic cells. Differentiating T-cells that recognise these antigens are then removed primarily by apoptotic clonal deletion, although some may survive by adopting alternative fates that have regulatory rather than autoreactive properties. These mechanisms thus prevent the autoimmune attack of peripheral organs. There is a clear match between the antigens that are ectopically expressed under the dictates of AIRE and the antigenic targets that manifest in its absence.

38
Q

AIRE and Disease

A

Eg. Autoimmune polyendocrinopathy syndrome type I
- Dysfunction of multiple endocrine glands
- Stems from mutations in AIRE genes
- Loss of tolerance
- Persistent fungal infections
- Affects parathyroid and adrenal gland

39
Q

Regulatory Element: FOXp3

A
  • FOXp3 (forkhead box P3)
  • Regulatory T-cell-master regulator
  • Transcriptional regulator
  • Development and function
  • Commitment to Treg phenotype from precursor cells
40
Q

Regulatory Element: Treg

A
  • Regulatory T-cells
  • Express CD4/CD25 and FOXp3
  • FOXp3 is critical in immune suppression
  • Mutations in FOXp3 gene - disease (IPEX)
  • Suppress activation, proliferation and cytokine production in CD4+/CD8+ T-cells
    Basic mechanisms used by Treg cells
  • Depiction of the various Treg cell mechanisms is centred around four basic modes of action
  • Inhibitory cytokines include interleukin-10 (IL-10), Il-35 and transforming growth factor-beta (TGF-beta)
  • Cytolysis includes granzyme-A and granzyme-B dependent and perforin-dependent killing mechanisms
  • Metabolic destruction includes high affinity CD25 (also known as IL-2 receptor), alpha-dependent cytokinedeprivation-mediated apoptosis, cyclick AMP (cAMP) mediated inhibition, and CD39+ and/or CD73-generated adenosine receptor 2A (A2AR)-mediated immunosuppression
  • Targeting dendritic cells induce mechanisms that modulate DC maturation and/or function such as lymphocyte-activation gene 3 (LAG3; also known as CD223)-MHC-class II mediated suppression of DC maturation, and cytotoxic T-lymphocyte antigen-4 (CTLA-4)-CD80/CD86-mediated induction of indoleamine 2,3-deoxygenase (IDO) which is an immunosuppresive molecule made by DCs
41
Q

Peripheral tolerance

A
  • Redundacny mechanism within the immune system
  • Circulating self-reactive B- and T-cells that survive tolerance
  • Regulates cells in peripheral tissues
  • Limit access to tissues and are inactivated
  • > Ignorance
  • > Potential autoantigens are hidden
  • Priveliged sites
  • Barriers prevent access
  • Eyes/CNS
  • > Regulation
  • HLA-B7 co-stimulator on APC membrane
  • Reguation of CTLA-4
  • Co-stimulation down-regulate T-cell function. Basic mechanisms of T-cell stimulation and inhibition
  • T-cell interaction begins with interaction of the T-cell receptor (TCR) on a T-cell with major histocompatibility complex (MHC) bound to antigen on an antigen-presenting cell (APC). This is known as signal 1, but appropriate activation of the T-cell requires additional signals that are provided by the interaction between CD28 and B7 (signal 2)
  • T-cell activation is limited by cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), which is upregulated on activated T-cells where it outcompetes CD28 for binding to B7 on an APC. Additional regulation of T-cell activity is also provided by later inhibitory signals through other molecules such as programmed cell death (PD1), which binds to PDL1 ligand (PDL1). Other regulators of T-cell activation have been characterised and may have important roles; these regulators include T-cell immunoglobulin and mucin domain-containing protein 3 (TIM3; also known as HAVCR2) and V-domain immunoglobulin suppressor of T-cell activation (VISTA)
42
Q

Suppression

A
  • Tregs suppress T-cell activity
  • Inhibitory cytokines (IL-10, TGF-beta)
  • CTLA-4
    Possible suppressive mechanisms of tumour environmental regulatory T-cells
    Multiple suppressive mechanisms rather than a single mode of action are proposed:
  • Treg cells are able to induce B7-H4 expression by antigen-presenting cells (APCs) and in turn these B7-H4 APCs induce T-cell cycle arrest through B7-H4
  • Activated human Treg cells directly kill target cells such as T-cells and APCs through perforin- or granzyme-B dependent pathways
  • Cytotoxic T-lymphocyte associated antigen (CTLA-4)+ Treg cells induce indoleamine 2,3-dioxygenase (IDO) expression by APCs, and IDO-expressing APCs suppress T-cell activation by reducing trytophan
  • Regulatory T-cells, including Treg cells, might release interleukine-10 (IL-10) and transforming growth factor (TGF-beta) in vivo, and directly inhibit T-cell activation and suppress APC function, by inhibiting expression of MHC molecules, CD80, CD86 and IL-12
43
Q

Anergy

A
  • Inactivation of T-cell following encounter with antigen
  • Lack of co-stimulatory molecules (HLA-B7)
  • Anergenic cells may undergo apoptosis
44
Q

Breakdown of tolerance

A
45
Q

Sequestered antigen exposure

A
  • Antigens hidden in ‘priveliged sites’ cant participate in tolerance:
  • > Thyroid colloid, testes, myelin, histone/DNA
  • > Priveliged sites have restricted/limited access for T-cells
  • Myelin basic protein hidden in Schwann cells may be released following an accident or bacteria and viral infection causing multiple sclerosis
  • Sperm antigens avoid early tolerance processes because sperm do not develop until puberty:
  • > antigen released during a vasectomy can cause auto-Ab formation
  • Eye trauma in one eye can cause sympathetic opthalmid (both eyes)
  • Auto-antibodies to type IV collagen in Goodpasture’s syndrome causes glomerulonephritis (kidney) in all patients
  • > Patients who smoke can also develop pulmonary problems because auto-antibodies can enter damaged lung tissue
46
Q

Molecular mimicry

A
  • Several viruses and bacteria possess antigenic peptide sequences (determinants) that are identical or similar to host-cell components:
  • > Klebsilla pneumonia nitrogenase (SRQTREDE)
  • > HLA-B27 molecule KATDREDL
  • Potential cause of ankylosing spendylitis (long-term condition in which the spine and other arease of the body are inflammed)
  • Heat shock proteins have been highly conserved throughout evolution and there are examples of heat-shock protein mimicry
  • > myobacterial Hsp65 and human Hsp60 in rheumatoid arthritis
47
Q

Causes, factors and transmission

A

Autoimmune disease transferred across the placenta to the foetus and newborn infant

Disease – Autoantibody – Symptom

Myasthenia Gravis – Anti-acetylcholine receptor – Muscle weakness
Graves Disease – Anti-thyroid-stimulating hormone (TSH) receptor – Hyperthyroidism
Thrombocytopenic purpura – Anti-platelet antibodies – Bruising and haemorrhage
Neonatal lupus rash and/or congenital heat block – Anti-ro and Anti-la antibodies – Photosensitive rash and/or bradycardia
Pemphigus vulgaris – Anti-desmoglein-3 – Blistering rash

  • Antibody-mediated autoimmune disease can appear in the infants of affected mothers as a consequence of transplacental antibody transfer
  • In pregnant women IgG antibodies cross the placenta and accumulate in the foetus before birth. Babies born to mothers with IgG-mediated autoimmune disease therefroe frequently show symptoms similar to those of the mother in the first few weeks of life. Fortunately, there is little lasting damage, as the symptoms disappear along with the maternal antibody. In Grave’s disease, the symptoms are caused by antibodies against the thyroid stimulating hormone (TSH) receptor. Children of mothers making thyroid-stimulating antibody are born with hyperthyroidism, but this can be corrected by replacing the plasma with normal plasma (plasmaphoresis) thus removing the maternal antibody.
48
Q

Genetic factors and autoimmune diseases

-

A
  • Several individuals in a family may develop an autoimmune disease because susceptibility is inherited (but the type of disease can vary)
  • HLA (human leukocyte antigen) is the dominant genetic factor that affects susceptibility
49
Q

Risk factors in autoimmunity

A
  • Hypersensitivity reactions
  • Failure to tolerate self-antigens involving mechanisms such as sequestered antigens, molecular mimicry, MHC-II expression
  • Bacterial or viral infections
  • Non-specific activation of T-cells and B-cells
  • Genetic susceptibility (inherited factors)
  • Endocrine factors (female predominance)
  • Adverse reactions to drugs
  • Ageing (immunosenescence)
50
Q

Hormonal risk factors

A
  • Most autoimmune diseases are caused in women
  • Exception: diabetes, male infertility, ankylosing spondylitis
  • Female sex hormones have a role in autoimmune diseases susceptibility but the mechanisms are not understood
  • > oestrogen inhibit cytotoxic/regulatory T-cells enabling T-cells to be activated and help B-cells to release antibody
  • Androgens may have a protective effect
51
Q

Drug risk factors

A

Some prescription drugs also appear to induce autoimmune disease:
- 15 - 20% taking procainamide (anti-arythmia drug) and 7-13% taking hydralazine (vasodilator) develop drug induced lupus
- drugs may cross-react or conjugate with host tissues
- drugs may reduce tolerance or sensitise immune cells
- drugs may effect macrophage antigen processing

52
Q

Age related factors

A
  • In young people, 1% of the T-cell population is replaced each day but this reduces with age
  • As the body ages, the size of the thymus decreases by 90% (involution)
    -> By the age of 50, new T-cell production has declined by 20%
    -> By the age of 70, new T-cell production has almost stopped
  • Senescence of the remaining T-cell clones contribute to autoimmunity because existing T-cell clones expand as the thymus fails to develop new T-cells and the frequency of autoimmunity increases
  • Stress, poor diet, lack of exercise, lack of sleep, abuse of alcohol and tobacco may affect the immune system and increase autoimmune risk
53
Q

Ageing and cells

A

Mast cells
- Decreased mast cell production
- Increase mast cell degranulation

NK cells
- Decreased cytotoxicity
- Decreased IL-2 production

Macrophages
- Decreased phagocytosis
- Increased inflammatory cytokines production

T-lymphocytes
- Increased memory CD8+ T-cells
- Decreased naive CD4+ T-cells

B-lymphocytes
- Decreased B-cell production

Neutrophils
- Decreased chemotaxis
- Decreased free radical production
- Decreased apoptosis

54
Q

Thymus involution

A

The thymic gland involutes with age

55
Q

Central tolerance

A
  • Thymocytes at different developmental stages are found in distinct parts of the thymus, the earliest cells to enter the thymus are found in the subcapsular region of the cortex. As these cells proliferate and mature into double positive thymocytes, they migrate deeper into the thymic cortex. Finally, the medulla contains only mature single positive T-cells which eventually leave the thymus and enter the bloodstream.
56
Q

Ageing and immunity

A

As we age, the strength of the immune response tips from the salutary environment to the inflammatory environment

Salutary environment
- B-cells
-> Robust secretion of high avidity antibodies
- CD8+, CD28+ T-cells
-> Diverse repertoire
-> Robust response to antigens

Inflammatory environment
- B-cells
-> Reduced antibody avidity and/or low responding cells
- CD8+ T-cells
-> Expansion of CD8+ and CD28 cells
-> Skewed repertoire
- CD4+ T-cells
-> Increased differentiation into Th17 cells

57
Q

Immunosenescence

A
  • More memory cells and less naive cells as we get older
58
Q

Inflammaging

A
  • Chronic low-grade inflammation
  • Absence of over infection
  • Risk factor for morbidity/mortality
  • Driver of normal ageing
59
Q

Summary of pathways in autoimmune diseases

A
60
Q

Treatment of autoimmune diseases

A
  • Current therapies are not cures
    -> The aim is to reduce symptoms and severity using drugs
  • Immuno-suppressant drugs are widely used:
    -> Corticosteroids
    -> Methetrexate
    -> Cyclophosphamide
  • Corticosteroids are the strongest drugs available for reducing inflammation, however, they have serious side effects at high doses. Their use may worsen infection resistance, high blood pressure, heart failure, diabetes, peptic ulcers and osteoporosis
  • A major problem with immunosuppressant drugs is that patiems become susceptible to infections and cancers

Disease-modifying anti-rheumatic drugs (DMARDs)
- Target the disease and not the symptoms
- Biological and conventional forms of DMARDs

61
Q

Summary

A
  • Autoimmune diseases are complex and diverse affecting an array of organ systems
  • Causes: 4 predominant causes: sequestered antigens, neoantigens, molecular mimicry, loss of immunoregulation
  • Mechanisms: tolerance
    -> Central tolerance from the perspective of T-cell generation, through positive and negative selection in the thymus
    -> Central tolerance from the perspective of B-cell generation, through positive and negative selection and B-cell receptor editing in the bone marrow
    -> Regulatory processes in central tolerance giving reference to the roles of autoimmune regulator (AIRE), Foxp3, CTLA4 and regulatory T-cells
    -> Peripheral tolerance giving reference to the role of ignorance, regulation (CTLA4), suppression (regulatory T-cells) and anergy
    -> Tolerance bypass mechanisms: sequestered antigens and molecular mimicry
  • Risk factors associated with autoimmunity in terms of genetics, drugs, hormonal, ageing

Immunology and Immunological Disorders (8 decks)

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