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3.Pathophysiology of AIDS,Autoimmune diseases and Hypersenstivity reactions

Presented by: Prof.Mirza Anwar BaigAnjuman-I-Islam's Kalsekar Technical Campus

School of Pharmacy,New Pavel,Navi Mumbai,Maharashtra

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Contents:

• Introduction

• Diagnosis

• Pathogesis

• Treatment

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What is AIDS:• Disease of the human immune system caused by the human

immunodeficiency virus (HIV).

• This condition progressively reduces the effectiveness of the immune system and leaves individuals susceptible to opportunistic infections and tumors.

• Routes of transmission: Unsafe sex, blood transfusion, contaminated hypodermic needles, exchange between mother and baby during pregnancy, childbirth, breastfeeding or other exposure to one of the above bodily fluids.

• Treatments can slow the course of the disease, there is currently no vaccine or cure. Antiretroviral treatment reduces both the mortality and the morbidity of HIV infection, but these drugs are expensive.

• Preventing infection is a key aim in controlling the AIDS pandemic, with health organizations promoting safe sex and needle-exchange programmes in attempts to slow the spread of the virus.

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Diagnosis

WHO disease staging system

Stage I: HIV infection is asymptomatic and not categorized as AIDSStage II: Includes minor mucocutaneous manifestations and

recurrent upper respiratory tract infectionsStage III: Includes unexplained chronic diarrhea for longer than a month, severe bacterial infections and pulmonary tuberculosisStage IV: Includes toxoplasmosis of the brain, candidiasis of the esophagus, trachea, bronchi or lungs and Kaposi's sarcoma; these diseases are indicators of AIDS.

Diagnostic tests:

1. Anti-HIV antibody (IgG and IgM) 2. HIV p24 antigen. 3. PCR test during the window period

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Basic Components of the Immune System

• Of the white blood cell pool, lymphocytes primarily drive the immune system.

• Lymphocytes (2 major types which protect host):

(1) B cells: formed in bone marrow and produce antibodies after exposure to an antigen.

(2) T cells: processed in the thymus (two subtypes)

Subtype 1: Regulator cells also known as helper or CD4 cells (“generals” in army of immune system which recognize “invaders” and summon armies of cells to mount a direct attack)

Subtype 2: Fighter or effector cells also known as cytotoxic or CD8 cells (bind directly to antigen and kill it)

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Basic Components of the Immune System

• 2 types of CD4 cells:

(1) Memory cells: those programmed to recognize a specific antigen after it has been previously seen

(2) Naïve cells: non-specific responders

• CD4 cells replicate 100 million times a day.

• CD4 cells are the target cells of HIV.

Bartlett, J.: The Johns Hopkins Hospital 2002 Guide to Medical Care of Patients with HIV Infection

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Pathophysiology of HIV/AIDSA retrovirus unknown until

early 1980s:

1.  Cannot replicate outside of living host cells

2. Contains only RNA; no DNA

3. Destroys the body’s ability to fight infections.

4. Infects CD4 cells – the primary target of HIV

infection

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CD4 Count in HIV infection1. Normal counts range from 500 to 1500 cells per cubic

millimeter of blood

2. Initially in HIV infection there is a sharp drop in the CD4 count and then the count levels off to around 500-600 cells/mm3. 

3. CD4 count is a marker of likely disease progression. CD4 percentage tends to decline as HIV disease progresses.

4. CD4 counts can also be used to predict the risks for particular conditions such as Pneumocystis carinii pneumonia disease.

5. Treatment decisions are often based on Viral Load and CD4 count.

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Natural History of Untreated HIV Infection

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AIDS Defined

1. HIV positive with a CD4 cell count that is or has been less than 200 cells/mm3

2. HIV positive with a CD4 percent below 14%.

3. HIV positive and with an AIDS defining illness such as PCP, toxoplasmosis, MAC, Kaposi’s Sarcoma, etc. regardless of CD4 cell count

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How HIV Drugs Work

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General Mechanisms of HIV Pathogenesis

Direct injury

Nervous (encephalopathy and peripheral neuropathy)

Kidney (HIVAN = HIV-associated nephropathy)

Cardiac (HIV cardiomyopathy)

Endocrine (hypogonadism in both sexes)

GI tract (dysmotility and malabsorption)

Indirect injury

Opportunistic infections and tumors as a consequence of immunosuppression

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Mechanisms of CD4 Depletion and Dysfunction

Direct

Elimination of HIV-infected cells by virus-specific immune responses

Loss of plasma membrane integrity because of viral budding

Interference with cellular RNA processing

Indirect

Apoptosis

Autoimmunity

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Antiretroviral Drugs Nucleoside Reverse Transcriptase

inhibitors AZT (Zidovudine)

Non-Nucleoside Transcriptase inhibitors Viramune (Nevirapine)

Protease inhibitors Norvir (Ritonavir)

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Pathophysiology of Autoimmune diseases

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Cells of the Immune System

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Reviewing the Cells of the Immune System

Lymphocyte

Eosinophil

Erythrocyte

Basophil

Neutrophil polymorph

Monocyte

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B Lymphocytes: Immunocompetency

occurs in bone marrow Produce Antibodies Conduct Humoral

Immunity

T Lymphocytes: Immunocompetency

occurs in thymus Non antibody producing

cells Conduct Cellular

Immunity

www.academic.brooklyn.cuny.edu/biology/bio4fv/page/aviruses/cellular-immune.html

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Autoimmune Diseases

Lymphocytes fail to recognize its own cells and tissues.

Autoantibodies and T cells to recognize own cells & launch attack against own cells

Perhaps due to overactive or an overabundance of helper T lymphocytes

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Examples of Autoimmune DiseasesMyasthenia gravis

Crohn’s disease

Grave’s disease

Type 1 Diabetes mellitus

Rheumatoid arthritis

Psoriasis

Scleroderma

Systemic lupus erythematosus

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What is the thyroid gland?

Butterfly-shaped endocrine gland

located in the lower front of the neck.

It make thyroid hormones, which are secreted into the blood and then carried to every tissue in the body.

Thyroid hormone helps the body use energy, stay warm and keep the brain, heart, muscles,and other organs working.

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What is Graves’ Disease?

Graves’ disease is caused by a generalizedoveractivity of the entire thyroid gland(hyperthyroidism). It is named for RobertGraves, an Irish physician, who describedthis form of hyperthyroidism about 150years ago.

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Epidemiology of Graves’ Disease

Cause of 50 – 80% of cases of hyperthyroidism

Prevalence: 0.6% of population

Female/male ratio: 5/1 – 10/1

Peak incidence: 40 – 60 years of age

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Pathophysiology:

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Pathogenesis of Graves’ Disease

• Autoreactive T cells and B cells emerge and

infiltrate the thyroid gland (as well as

extrathyroidal tissues) and elaborate various cytokines that ultimately lead to production of TSH receptor antibodies (TSHRAb) as a result of:

• Genetic susceptibility

• Environmental factors - infections, stress, smoking ,female gender

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The Classic Triad of Graves’ Disease

Hyperthyroidism (90%)

Ophthalmopathy (20-40%)

ophthalmoplegia, conjunctival irritation

3-5% of cases require directed treatment

Dermopathy (0.5-4.3%)

localized myxedema, usually pretibial

especially common with severe

ophthalmopathy

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Syndrome of Hyperthyroidism

Weight loss, heat intolerance

Thinning of hair, softening of nails

Stare and eyelid lag

Palpitations, symptoms of heart failure

Dyspnea, decreased exercise tolerance

Diarrhea

Frequency, nocturia

Psychosis, agitation, depression

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Graves’ Ophthalmopathy

Antibodies to the TSH receptor also target retroorbital tissues

T-cell inflammatory infiltrate -> fibroblast growth

Severe: exposure keratopathy, diplopia, compressive optic neuropathy

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Myxedema of Graves’

Activation of fibroblasts leads to increased hyaluronic acid and chondroitin sulfate

Asymmetric, raised, firm, pink-to-purple, brown plaques of nonpitting edema

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Laboratory Evaluation Suppressed TSH (<0.05 uU/ml) Elevated Free T4 and/or Free T3

T3:T4 > 20- Graves’ Disease- Toxic Goiter

T3:T4 < 20- Non-thyroid illness- Thyroiditis- Exogenous thyroxine

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Laboratory Evaluation Direct measurement of TSH receptor

antibodies (TSAb and TBAb) Can help with Graves diagnosis in

confusing cases (as high as 98% sensitivity)

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Immediate Medical Therapy Thionamides – inhibit central production of T3 and T4; immunosuppressive effect Methimazole – once daily dosing

PTU – added peripheral block of T4 to T3 conversion; preferred in pregnancy

Side effects: hives, itching; agranulocytosis, hepatotoxicity, vasculitis

Beta-blockade – decrease CV effects

High-dose iodine – Wolff-Chaikoff effect

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Long-term Therapeutic Options

Continued Medical Management Low dose (5-10mg/day of methimazole) for

12 to 18 months then withdraw therapy

Radioiodine Ablation Discontinue any thionamides 3-5 days prior

Overall 1% chance of thyrotoxicosis exacerbation

Hypothyroidism in 10-20% at 1 yr, then 5% per yr

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Long-term Therapeutic Options

Total Thyroidectomy Recent metaanalysis showed this is the

most cost effective. Prep with 6 weeks thionamides, 2 weeks

iodide Hypoparathyroidism and/or laryngeal

nerve damage in <2% Lasting remission in 90%

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Management of Graves’ OphthalmopathyAcute Active Phase

dark lenseselevate head of bedartificial tears & ointmentsdiureticsprisms for diplopiaglucocorticoids &/or orbital radiotherapy for severe diseasesurgical followed by 131I ablation for severe disease

Chronic Inactive Phaseeye muscle surgeryeyelid surgery

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Treatment of OphthalmopathyMild Symptoms

Eye shades, artificial tears

Progressive symptoms (injection, pain) Oral steroids – typical dosage from 30-

40mg/day for 4 weeks

Impending corneal ulceration, loss of vision Oral versus IV steroids

Orbital Decompression surgery

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Pathophysiology of Rheumatoid Arthritis

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What is Rheumatoid arthritis (RA, rheumatoid disease)

A chronic progressive inflammatory autoimmune disease.

Systemic disorder where inflammatory changes not only

affect synovial joints but also many other sites including

the heart, blood vessels and skin.

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Epidemiology

Systemic inflammatory autoimmune disorder

~1% of population

Onset:

40-70 years of age

3-5:1 - female predominance

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Causes and risk factors 1. The cause of RA is unknown.

2. Infectious agents such as viruses, bacteria, and fungi have long been suspected.

3. It may be genetically inherited (hereditary).

4. Certain infections or factors in the environment might trigger the activation of the immune system. This misdirected immune system then attacks the body's own tissues.

5. This leads to inflammation in the joints and sometimes in various organs of the body, such as the lungs or eyes.

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Symptoms and signs1. Fatigue, loss of energy, lack of appetite , low-grade fever,

muscle and joint aches, and stiffness.

2. Muscle and joint stiffness are usually most notable in the morning and after periods of inactivity.

3. Also during flares, joints frequently become red, swollen, painful. This occurs because the lining tissue of the joint (synovium) becomes inflamed, resulting in the production of excessive joint fluid (synovial fluid).

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Joints involved in rheumatoid arthritis, include

The most common joints involved are;

• Wrists and

• The index (2nd) and middle (3rd) metacarpophalangeal (MCP) joints

Other joints include;

1. Proximal interphalangeal (PIP) joints

2. Metatarsophalangeal (MTP) joints

3. Shoulders

4. Elbows

5. Hips

6. Knees

7. Ankles

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Irreversible Joint Deformities may occur due to disease progression.

They include:

1. Ulnar deviation of the fingers2. Boutonniere Deformity 3. Swan Neck Deformity

Extra-articular Manifestations

• RA is a systemic disease that involves other organs. Most of rheumatoid arthritis extra-articular manifestations are collected in this image related to the involved organ.

• Subcutaneous rheumatoid nodules develop in 20% of patients, usually at sites of pressure and chronic irritation (eg, the extensor surface of the forearms, elbows, hands, and feet).

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Diagnosis

• No singular test for diagnosing rheumatoid arthritis.

• It is diagnosed based on a combination of the presentation of the joints involved, characteristic joint stiffness in the morning, the presence of blood rheumatoid factor.

• Findings of rheumatoid nodules and radiographic changes (X-ray testing).

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Camparison of normal and arthritic joints

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Pathogesis:

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TreatmentMedications to Reduce Pain and Inflammation

1) Non-Steroidal Anti-inflammatory Drugs (NSAIDs)e.g., ibuprofen, naproxen, ketoprofen, piroxicam, and

diclofenac2) COX-2 inhibitor (only celecoxib)3) Low-dose systemic corticosteroids (CS)Medications to Prevent Disease Progression & loss ofjoint function1) Disease-modifying antirheumatic drugs (DMARDs)

include: methotrexate (MTX), hydroxychloroquine (HCQ), azathioprine (AZA),

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Pathophysiology of Myasthenia gravis

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Myasthenia gravis

1. A long term neuromuscular disease that leads to varying degrees of muscle weakness.

1. An autoimmune disease which results from antibodies that block acetylcholine receptors at the junction between the nerve and muscle. This prevents nerve impulses from triggering muscle contractions.

3. The most commonly affected muscles are those of the eyes, face, and swallowing.

4. It can result in double vision, drooping eyelids, trouble talking, and trouble walking. Onset can be sudden.

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Epidemiology:

• Myasthenia gravis occurs in about 1 in 10,000 people.

• More common in women, typically ages 20 to 40 at onset; men usually are ages 50 to 60 at onset.

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Etiology:The following factors may trigger or worsen exacerbations:

1. Bright sunlight

2. Surgery

3. Immunization

4. Emotional stress

5. Menstruation

6. Intercurrent illness (eg, viral infection)

7. Medication (eg, aminoglycosides, ciprofloxacin, chloroquine,

procaine, lithium, phenytoin, beta-blockers, procainamide, statins)

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Diagnosis:

1. Anti–acetylcholine receptor (AChR) antibody test

2. Plain chest radiographs

3. Chest computed tomography

4. Magnetic resonance imaging of the brain and orbit

5. Electrodiagnostic studies (repetitive nerve stimulation and single-

fiber electromyography)

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Pathogenesis:

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Pathogenesis:• With every nerve impulse, the amount of ACh released by the presynaptic

motor neuron normally decreases because of a temporary depletion of the presynaptic ACh stores (a phenomenon referred to as presynaptic rundown).

• In MG, there is a reduction in the number of AChRs available at the muscle endplate The end result is inefficient neuromuscular transmission.

• Inefficient neuromuscular transmission together with the normally present presynaptic rundown phenomenon results in a progressive decrease in the amount of muscle fibers being activated by successive nerve fiber impulses. This explains the fatigability seen in MG patients.

• Patients become symptomatic once the number of AChRs is reduced to approximately 30% of normal. The cholinergic receptors of smooth and cardiac muscle have a different antigenicity than skeletal muscle and usually are not affected by the disease.

• MG can be considered a B cell–mediated disease. However, the importance of T cells in the pathogenesis of MG is becoming increasingly apparent. The thymus is the central organ in T cell–mediated immunity, and thymic abnormalities such as thymic hyperplasia or thymoma are well recognized in myasthenic patients.

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Treatment:

1. Acetylcholine esterase (AChE) inhibitors

include pyridostigmine, neostigmine, and edrophonium.

2. Immunomodulating therapy

Example: Corticosteriod therapy,azathioprine, mycophenolate mofetil, cyclosporine, cyclophosphamide, and rituximab

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Hypersensitivity Reactions

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Hypersensitivity and types of hypersensitivity reactions.

• Allergic or hypersensitive person : A person who is overly reactive to a substance that is tolerated by most other people.

• Allergy: Is a powerful immune response to an antigen (allergen).The allergen itself is usually harmless .

• Common allergens include certain foods (milk, peanuts, shellfish, eggs), antibiotics (penicillin, tetracycline), vaccines (typhoid), venoms (honeybee, snake), cosmetics, chemicals in plants such as pollens, dust, molds, iodine-containing dyes used in certain x-ray procedures, and even microbes.

• Immune response that causes the damage to the body, not the allergen itself.

• Upon initial exposure to the allergen the individual becomes sensitised to it, and on second and subsequent exposures the immune system mounts a response entirely out of proportion to the perceived threat.

• These responses are exaggerated versions of normal immune function. Sometimes symptoms are mild, e.g. the running nose and streaming eyes of hay fever. Occasionally the reaction can be extreme,and causing death.

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Types of hypersensitivity reactions

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Allergic reactions

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