Tolerance
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Tolerance. Tolerance differs from immunosuppression in that tolerance is antigen-specific, while immunosuppression is not. A person can be immunologically non-responsive (tolerant) to a single antigen, while being able to respond to all other antigens he or she encounters.

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Tolerance

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Tolerance

Tolerance

Tolerance differs from immunosuppression in that tolerance is antigen-specific, while immunosuppression is not. A person can be immunologically non-responsive (tolerant) to a single antigen, while being able to respond to all other antigens he or she encounters.

In contrast, a person who is immunosuppressed has difficulty responding to any and all antigens.

Only T and B cells can be tolerized


Tolerance to self antigens

Tolerance to Self Antigens

  • Central tolerance

    • Achieved by clonal deletion (apoptosis) of

      • Self-reactive T cells in the thymus

      • Self-reactive B cells in the bone marrow

    • Some self-reactive T cells mature into Tregcells that prevent autoimmune reactions

  • Peripheral tolerance

    • T cell anergy

      • T cell remains alive but is inactivated when it engages APC lacking B7 co-stimulatory molecule

      • Self-reactive T cell is suppressed by Treg cell

    • B cell anergy

      • Doesn’t get help it needs from TH

      • Immature B cells become anergic when surface IgM engages antigen


Peripheral tolerance immunological privilege

Peripheral Tolerance: Immunological Privilege

  • Privileged tissues

    • Brain

    • Anterior chamber of the eye

    • Ovary

    • Placenta

    • Testis

    • Pregnant uterus

  • Protected from T cells by impervious membranes, e.g. blood-brain barrier

  • Low levels of complement and high TGF

  • Express FasL


Autoimmunity

Autoimmunity

  • Immune response to self antigen

  • Due to failures in central and peripheral tolerance

  • Factors contributing to autoimmunity

    • Inheritance of MHC susceptibility genes

– Environmental triggers – infection, injury, inflammation

• HLA used as microbe receptor

• Microbe shows molecular mimicry with HLA molecule

-Microbe is seen as “self” and escapes detection

- Microbe might “break tolerance” to self tissues → autoimmunity

• Trauma introduces privileged tissues to immune system


Autoimmune diseases

Autoimmune Diseases

  • Organ-specific autoimmune diseases

    • Pernicious anemia, Goodpasture’s syndrome, type 1 diabetes mellitus, myasthenia gravis, Addison disease, bullous diseases (pemphigus vulgaris and bullous pemphigoid), Graves disease (thyrotoxicosis), Hashimoto’s thyroiditis

  • Non-organ specific autoimmune diseases

    • Rheumatoid arthritis, SLE, Sjögren’s syndrome, Guillain-Barré syndrome, MS


Pernicious anemia stomach

Pernicious Anemia (Stomach)

  • Megaloblastic anemia caused by B12 malabsorption

  • Inability to secrete intrinsic factor, a cofactor in B12 absorption

  • Antibodies to intrinsic factor/parietal cells cause parietal cell loss

  • May be associated with chronic Helicobacter pylori infection

  • Usual onset older than 30 years

Megaloblast in bone marrow

Abs to parietal cells

Oval macrocytes

Hypersegmented PMN nucleus


Pernicious anemia stomach1

Pernicious Anemia (Stomach)

  • Signs and symptoms

    • Beefy, red, smooth, sore tongue

    • Weakness, dyspnea, anorexia, fever, diarrhea

    • Neurological: numbness, tingling, weakness, clumsiness, unsteady gait

    • "Megaloblastic madness": delusions, hallucinations, outbursts, paranoia

    • Severe gastric gland atrophy, achlorohydria, gastric adenocarcinoma 3X normal

  • Treatment

    • Depot vitamin B12


Goodpasture s syndrome lungs kidneys

Goodpasture’s Syndrome (Lungs, Kidneys)

  • Complement-fixing autoantibodies directed toward type IV collagen found in the basement membranes of pulmonary alveoli and glomerular capillaries

  • Linear deposition of antibody and complement causes pulmonary hemorrhage (usual cause of death) and progressive glomerulonephritis

  • Acute phase treatment: intubation, assisted ventilation, hemodialysis

Homogenous, ribbon-like staining with anti-IgG demonstrates presence of IgG bound to collagen in glomerular basement membrane


Goodpasture s syndrome lungs kidneys1

Goodpasture’s Syndrome (Lungs, Kidneys)

  • Longer-term management

    • High-dose corticosteroids (methylprednisolone)

    • Immunosuppression with cyclophosphamide

    • Plasmapheresis to remove anti-glomerular basement membrane antibodies from the circulation

  • End-stage renal disease can be managed by long-term hemodialysis or kidney transplantation

  • HLA-DR2 linkage

Immunoadsorption-type plasmapheresis


Insulin dependent diabetes mellitus pancreas

Insulin-dependent Diabetes Mellitus (Pancreas)

  • Type 1 diabetes, juvenile-onset diabetes

  • Multisystem disease marked by altered glucose, fat, and protein metabolism due to impaired insulin production

  • Peak age at onset 11-12 years

  • Cell-mediated immune destruction of insulin-producing  cells in the islets of Langerhans

    • TH1 activate Tc and MΦ

    • MΦ produce ROIs, NO, TNF, and IL-1 that damage tissue

    • Tc kill  cells directly by perforin, granzymes, FasL

    •  cells are most sensitive because they display Fas

    • TH17 cells play role

  • Autoantibodies to islet cells and insulin may predict course of disease


Insulin dependent diabetes mellitus pancreas1

Insulin-dependent Diabetes Mellitus (Pancreas)

  • 50% are HLA-DR3/DR4 heterozygotes

  • Viral infection may play role – rubella, mumps, Coxsackie B

  • Signs and symptoms

    • Ketoacidosis

    • Polyuria and thirst

    • Polyphagia with weight loss

    • Fatigue, weakness, muscle cramps

    • Blurred vision

    • Nausea, abdominal discomfort or pain, change in bowel movements

    • Right upper quadrant GI pain due to distension of fatty liver

    • Peripheral neuropathy presenting as numbness and tingling in both hands and feet in a glove and stocking pattern

Abs to  cells


Insulin dependent diabetes mellitus pancreas2

Insulin-dependent Diabetes Mellitus (Pancreas)

  • Chronic complications

    • Atherosclerosis leading to ischemic necrosis of limbs and organs

    • Microvascular obstruction leading to

      • Retinal damage/vision loss

      • Renal damage

      • Peripheral neuropathy

    • Repeated infections

  • Management

    • Diet and exercise

    • Treat symptoms with insulin


Myasthenia gravis muscles

Myasthenia Gravis (Muscles)

  • Autoantibodies (alone or with complement) are directed toward the acetylcholine receptors in the motor end plates of neuromuscular junctions

    • Muscle fatigability (especially after exercise)

    • Progressive muscular weakness

      • Difficulty in chewing, swallowing and breathing

      • Diplopia (double vision) and ptosis (droopy eyelids)


Myasthenia gravis muscles1

Myasthenia Gravis (Muscles)

  • Most common in women; usually develops between 20 and 40 y of age but may develop at any age

  • Treatment

    • Cholinesterase inhibitors (e.g., pyridostigmine)

    • Corticosteroids (e.g., prednisone)

    • Immunosuppressive drugs (e.g., azathioprine)

    • Intravenous immune globulin

    • Plasmapheresis (do not combine with IVIG)

    • Thymectomy

  • Neonatal myasthenia

    • Generalized muscle weakness affecting 12% of infants born to women with myasthenia gravis

    • Passively transferred IgG

    • Symptoms resolve in days to weeks as antibody titers decline


Addison s disease adrenal glands

Addison’s Disease (Adrenal Glands)

  • Autoantibodies against adrenocorticotropic hormone (ACTH) receptors or other cortex antigens on the adrenal glands

  • Inadequate secretion of corticosteroids, e.g. cortisol

  • Destruction of adrenal cortex leads to overproduction of corticotropin and melanocyte-stimulating hormone

  • Signs and symptoms

    • Weight loss, diarrhea, vomiting, abdominal pain

    • Muscle weakness, fatigue, low blood pressure

    • Darkening of the skin in both exposed and nonexposed parts of the body

    • Depression, irritability, loss of concentration

  • Treat by hormone replacement (e.g. cortisone)


Addison s disease

Addison’s Disease


Bullous diseases skin and or mucosa

Bullous Diseases (Skin and/or Mucosa)

  • Complement and autoantibodies to skin components are deposited in squamous intercellular spaces and along basement membrane of skin

  • Pemphigus vulgaris

    • Erosion of the skin and mucous membranes with flaccid intraepithelial blisters; blisters are painful but rarely itch

    • Deposition of IgG autoantibodies to keratinocyte cell surface desmogleins; results in a loss of cell-cell adhesion (acantholysis)

    • Treat with prednisone, immunosuppressives, or plasmapheresis


Bullous diseases skin and or mucosa1

Bullous Diseases (Skin and/or Mucosa)

  • Bullous pemphigoid

    • Chronic subepidermal blistering skin disease that rarely involves mucous membranes

    • Blisters are tense, and can be preceded by itchy urticarial lesions

    • IgG antibodies to hemidesmosomal antigens of the skin basement membrane fix complement

    • Eotaxin is strongly expressed in the basal layer of the epidermis of lesions – recruits eosinophils

    • Onset ~65 years

    • Treat with prednisone, immunosuppressives, tetracycline, Rituximab to CD20

Linear IgG along dermoepidermal junction


Graves disease thyrotoxicosis thyroid

Graves Disease/Thyrotoxicosis(Thyroid)

  • Autoantibodies against the receptor for thyroid stimulating hormone (TSH) continuously stimulate the thyroid gland

  • Hyperthyroidism due to T3 and T4 overproduction

  • Autoantibodies may also be produced to thyroperoxidase and thyroglobulin; these antibodies are also seen in patients with Hashimoto thyroiditis

  • The disease most commonly affects women in their thirties and forties, with a female:male ratio of about 7:1

  • Treat with anti-thyroid drugs (e.g., methimazole, propylthiouracil), radioactive iodine, thyroid surgery


Graves disease thyrotoxicosis thyroid1

Graves Disease/Thyrotoxicosis(Thyroid)

  • Signs and symptoms

    • Goiter

    • Rapid heart rate, palpitations, widened pulse pressure

    • Hyperthyroid stare (infrequent blinking) or frank exophthalmos

    • Tremor, sweating, smooth moist skin

    • Frequent bowel movements or diarrhea, weight loss

    • Sleeplessness, attention problems, irritability

    • Pretibial myxedema


Tolerance

Graves Disease/Thyrotoxicosis(Thyroid)

Goiter and thyrotoxic stare

Exophthalmos


Tolerance

Graves Disease/Thyrotoxicosis(Thyroid)

Pretibial myxedema (orange peel skin) and goiter


Hashimoto thyroiditis thyroid

Hashimoto Thyroiditis (Thyroid)

  • TH1 infiltration of the thyroid gland mediates its destruction

  • Hypothyroidism

  • Autoantibodies to thyroglobulin, thyroid peroxidase, thyroid epithelial cell microsomal antigen, cell surface antigen, and colloid

  • Goiter forms in response to leukocyte infiltration that replaces thyroid cells

A dense infiltrate of plasma cells and lymphocytes with germinal center formation is seen in this thyroid


Hashimoto thyroiditis thyroid1

Hashimoto Thyroiditis (Thyroid)

  • Signs and symptoms

    • Fatigue, memory deficits

    • Constipation

    • Dry skin, decreased sweating, cold intolerance

    • Weight gain

    • Hoarseness

    • Mild nerve deafness

    • Joint pain, muscle cramps

    • Menstrual irregularities

  • Treat with thyroxine

Thyroid scan after 127I uptake


Rheumatoid arthritis ra

Rheumatoid Arthritis (RA)

  • Destructive disease of the joints, particularly of the fingers, as well as larger joints including wrists, ankles, knees, elbows, and shoulders

  • Signs and symptoms

    • Morning stiffness

    • Arthritis of 3 or more joint areas

    • Subcutaneous rheumatoid nodules over bony prominences or extensor surfaces or in juxta-articular regions


Rheumatoid arthritis ra1

Rheumatoid Arthritis (RA)

  • Signs and symptoms continued

    • Serum rheumatoid factor (RF)

      • 70-90% of patients have circulating RF, an antibody that is reactive with the Fc fragment of IgG

      • RF plays a secondary role in joint pathology by fixing complement

      • RF is also elevated in other rheumatic diseases – not pathognomonic for RA

    • Changes on hand and wrist radiographs

      • Erosions or bony decalcifications

RF


Rheumatoid arthritis ra2

Rheumatoid Arthritis (RA)

  • Inflammatory TH1 cells activate resident synovial cells to produce hydrolytic enzymes and cytokines, including IL-1 and TNF

  • The hydrolytic enzymes destroy cartilage, ligaments and tendons

  • TH17 cells may play a role: IL-17 exerts synergistic effects with TNF and IL-1 in the induction of joint inflammation and cartilage and joint destruction

  • Initial trigger may be diverse

    • Epstein-Barr virus

    • Bacterial heat shock proteins recognized by  T cells

    • Mycobacterial infection


Rheumatoid arthritis ra3

Rheumatoid Arthritis (RA)

  • 30% of RA patients have elevated titers of anti-nuclear antibodies

  • RA affects up to 1% of the population with a 3:1 preponderance of females:males

  • HLA-DR4 linkage

  • Treatment depends on severity of symptoms

    • OTC non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen

    • Corticosteroids like prednisone that inhibit macrophages

    • COX-2 inhibitors like Celebrex that block prostaglandin synthesis


Rheumatoid arthritis ra4

Rheumatoid Arthritis (RA)

  • Treatment continued

    • Xenobiotics like gold salts, D-penicillamine, and chloroquine

    • Inhibitors of nucleic acid synthesis such as azathioprine and cyclophosphamide

    • Anti-TNF agents

      • Monoclonal antibodies Infliximab/Remicade and Adalimumab/Humira

      • Soluble TNF receptor genetically linked to the Fc portion of human IgG – Etanercept/Enbrel

      • Antagonists for IL-1R and the B7 costimulatory molecule


Systemic lupus erythematosus sle

Systemic Lupus Erythematosus (SLE)

  • Immune complexes composed of self DNA or nucleoprotein antigens, antibodies and complement are deposited in the skin, kidneys and joints, yielding a lumpy-bumpy pattern on immunofluorescence

  • Additional autoantibodies against RNA, red blood cells, platelets, mitochondria, ribosomes, lysosomes, thromboplastin, and thrombin

IC lodged in glomeruli

Anti-nuclear antibodies


Systemic lupus erythematosus sle1

Systemic Lupus Erythematosus (SLE)

  • Signs and symptoms

    • Erythema, glomerulonephritis, and arthritis

    • A major sign is the malar rash (butterfly rash) over the nose and cheeks

    • Mild cases: fever, arthritis, pleurisy, pericarditis, headache, or rash

    • Severe cases: life-threatening hemolytic anemia, thrombocytopenic purpura, massive pleural and pericardial involvement, significant renal damage, acute vasculitis of the extremities or GI tract, florid CNS involvement

Discoid skin rash

Butterfly rash


Systemic lupus erythematosus sle2

Systemic Lupus Erythematosus (SLE)

  • 90% of SLE patients have elevated titers of anti-nuclear antibodies (ANA)

  • 20% of SLE patients have elevated RF titers

  • 90% of patients are women

  • Most common age of onset is 20-40 years

  • HLA-DR2 and HLA-DR3 linkage

  • Associated with C2 and C4 deficiency in 10% of cases

  • Management

    • Avoid sunlight to prevent flairs

    • Control arthralgias with NSAIDs such as aspirin, or COX-2 inhibitors if GI bleeds are a concern

    • Antimalarials

    • Prednisone and immunosuppressive drugs (azathioprine, cyclophosphamide) for active CNS lupus or reversible lupus nephritis

  • In clinical trials: Mabs to CD40L, CD20, and B7


Sj gren syndrome sicca syndrome

Sjögren Syndrome (Sicca Syndrome)

  • Chronic inflammatory disease mediated by a CD4+ TH cell infiltrate affecting the exocrine glands (primarily the lacrimal and salivary glands)

  • Signs and symptoms

    • Dry eyes (keratoconjunctivitis sicca)

    • Dry mouth (xerostomia)

    • Dry vaginal mucosa

    • Sometimes dry nose, larynx, and bronchi


Sj gren syndrome sicca syndrome1

Sjögren Syndrome (Sicca Syndrome)

  • Usually associated with another connective tissue disease such as RA or SLE

  • RF and anti-nuclear antibodies present in 70% of patients

  • Syndrome is not life-threatening but up to 13% of patients progress to lymphoma

  • Treatment is usually symptomatic

Enlargement of the salivary gland in a patient with sicca syndrome


Guillain barr syndrome gbs acute idiopathic polyneuritis

Guillain-Barré Syndrome (GBS)(Acute Idiopathic Polyneuritis)

  • An ascending paralysis that affects the peripheral nerves

  • Collection of clinical syndromes manifested by an acute inflammatory polyradiculoneuropathy with resultant weakness and diminished reflexes

    • Paresthesia, numbness, facial droop, double vision, dysphagia, dysarthria

    • Assisted ventilation may be needed

  • Most important cause of acute flaccid paralysis in countries without polio


Guillain barr syndrome gbs

Guillain-Barré Syndrome (GBS)

  • Commonly occurs after an infectious disease (e.g. Campylobacter jejuni, CMV, EBV, VZV, and Mycoplasma pneumoniae) or vaccination (e.g., influenza)

  • Most common antecedent infection is Campylobacter jejuni

  • Immune response directed toward the infecting microorganism cross-reacts with neural tissues

    • Molecular mimicry with gangliosides and glycolipids, such as GM1 and GD1b, distributed throughout the myelin in the peripheral nervous system

    • Although anti-nerve antibodies are produced, it is the inflammatory cellular response that leads to pathology


Guillain barr syndrome gbs1

Guillain-Barré Syndrome (GBS)

  • Guillain-Barré syndrome is a medical emergency, requiring constant monitoring and support of vital functions

    • Corticosteroids worsen the outcome and should not be used

    • Keep airway clear, assist respiration if necessary

    • Plasmapheresis to remove autoAbs

    • Daily infusions of IVIG can be used instead of plasmapheresis

    • The potassium channel blocker 4-aminopyridine (4-AP) to improve nerve conduction across demyelinated axons

    • Physical and speech therapy


Multiple sclerosis ms

Multiple sclerosis (MS)

  • A chronic or relapsing paralysis that affects the central nervous system

  • The most common neurologic disease of young adults, peak incidence 35 years

  • 2:1 female:male incidence

  • Demyelination of central nervous system tissue

    • Inflammatory TH1 cells specific for myelin basic protein recruit effector cells – Tc, macrophages, and microglia

    • Effector cells attack oligodendrocytes (the major cells comprising the myelin sheath) that display Fas

    • Initiating inflammatory stimulus may involve infection by a virus (human herpes virus or HTLV-1) displaying molecular mimicry to a neuroepitope

    • TH17 cells play a role


Multiple sclerosis ms1

Multiple sclerosis (MS)

  • Remissions and recurrences of these signs may occur months or years before the disease is recognized:

    • Paresthesias (prickling, tingling) in one or more extremities, in the trunk, or on one side of the face

    • Weakness or clumsiness of a leg or hand

    • Partial blindness and pain in one eye or dimness of vision

    • Difficulty with bladder control

    • Vertigo

    • Mild emotional disturbances, apathy, lack of judgment

    • Excess heat (e.g., warm weather, a hot bath, a fever) may accentuate symptoms and signs


Multiple sclerosis ms2

Multiple sclerosis (MS)

  • Lab results

    • MRI: plaques of demyelination with perivascular inflammation are disseminated throughout the CNS, primarily in the white matter. The gray matter in the cerebrum and spinal cord may also be affected

    • Contrast-enhanced CT may also detect MS lesions


Multiple sclerosis ms3

Multiple sclerosis (MS)

  • Lab results

    • Cerebrospinal fluid (CSF) is abnormal in the majority of patients

      • Oligoclonal IgG bands detected by agarose electrophoresis of CSF in up to 90% of patients with MS

      • Absence of IgG bands does not rule out MS

      • IgG levels correlate with disease severity

      • Myelin basic protein may be elevated during active demyelination


Multiple sclerosis ms4

Multiple sclerosis (MS)

  • Treatments

    • Corticosteroids (methylprednisolone)

    • ABC therapy – reduces the frequency of relapses in MS and may help delay eventual disability

      • Avonex (interferon -1a): increases IL-10 that down-regulates TH1

      • Betaserone (interferon -1b): prevents IFN up-regulation of class II MHC on oligodendrocytes

      • Copaxone – synthetic polypeptide of alanine, glutamic acid, lysine, tyrosine

        • Prevents loading of processed myelin peptides into the grooves of HLA-DR molecules

        • Induces Treg cells that down-regulate the inflammatory response


Multiple sclerosis ms5

Multiple Sclerosis (MS)

  • Treatments continued

    • Regular exercise is recommended, even for patients with more advanced disease

    • Physical therapy for gait training and range-of-motion exercises for weak, spastic limbs helps


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