Pathophysiology of AIDS,Autoimmune diseases and hypersensitivity reactions

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3.Pathophysiology of AIDS,
Autoimmune diseases and
Hypersenstivity reactions
Presented by: Prof.Mirza Anwar Baig
Anjuman-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 AIDS
Stage II: Includes minor mucocutaneous manifestations and
recurrent upper respiratory tract infections
Stage III: Includes unexplained chronic diarrhea for longer than a
month, severe bacterial infections and pulmonary
tuberculosis
Stage 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 In

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Pathophysiology of HIV/AIDS
A 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 infection
1. 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/cellula
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 Diseases
Myasthenia 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 generalized
overactivity of the entire thyroid gland
(hyperthyroidism). It is named for Robert
Graves, an Irish physician, who described
this form of hyperthyroidism about 150
years 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’ Ophthalmopathy
Acute Active Phase
dark lenses
elevate head of bed
artificial tears & ointments
diuretics
prisms for diplopia
glucocorticoids &/or orbital radiotherapy for
severe disease
surgical followed by 131I ablation for severe
disease
Chronic Inactive Phase
eye muscle surgery
eyelid surgery

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Treatment of Ophthalmopathy
 Mild 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 signs
1. 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 fingers
2. 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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Treatment
Medications to Reduce Pain and Inflammation
1) Non-Steroidal Anti-inflammatory Drugs (NSAIDs)
e.g., ibuprofen, naproxen, ketoprofen, piroxicam, and
diclofenac
2) COX-2 inhibitor (only celecoxib)
3) Low-dose systemic corticosteroids (CS)
Medications to Prevent Disease Progression & loss of
joint function
1) 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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