Immunopathology A26-A33

Question 1

A/26. Type I-II. hypersensitivity reactions. Clinical and pathologic manifestations

What is the type 1 reaction, what are the chemical mediators of it.

Answer 1

Type 1, IgE mediated hypersensitivity. anaphylaxis reaction.

First exposure:

1. Foreign antigen enters body.
2. APCs present antigen
3. T-h cells release IL-4 and IL-5.
4. B-cells produce IgE
5. Mast cells and basophils coat themselves with IgE

Second exposure

1. Degranulation

Primary mediators: Vasodilation, Bronchospasms, Granulocyte Recruitment.

1. Histamine, Serotonin, Bradykinin

Secondary mediators:

1. Leukotrienes,
2. PDGF
3. TNF-alpha

Late Phase:

1. Eiosinophils accumulate at the site, and release a second wave of dilators and inflammatory cytokines, as well as Major Basic Protein.
2. Major Basic Protein, basophil mediated destruction of the cell

Question 2

A/26. Type I-II. hypersensitivity reactions. Clinical and pathologic manifestations

What are the clinical examples of type 1 hypersensitivity reactions

Answer 2

1. Allergic Rhinitis, hay fever.
2. Food Allergies
3. Contact Dermatitis
4. Athsma Bronchiale - Extrinsic athsma. - expiratory dyspnea
5. Systemic anaphylaxis, anaphylactic shock.
   
   • general edema, itching, vomiting, diarrhea
   • lung edema and ARDS
   • asphyxia

-skin scratch with penicillin

Question 3

A/26. Type I-II. hypersensitivity reactions. Clinical and pathologic manifestations

What is a type 2 hypersensitivity response?

What are the clinical examples?

Answer 3

IgG or IgM mediated antibody response.

Antibodies are directed against a cell surface bound antigen.

Antibodies produce cell toxicity by all of their various means. If it is a blood cell antibody, this will cause systemic inflammation as well.

Clinical examples:

ABO and Rh incompatibility, Hydrops Fetalis.

Question 4

A/27. Type III-IV. hypersensitivity reactions. Clinical and pathologic manifestations

What are type 3 hypersensitivity reactions?

What are the main factors that determine the pathogenicity?

Answer 4

Immune complex mediated reaction.

IgM or IgG mediated reaction against a soluble circulating antigen.

Large immune complexes with many exposed Ig regions: are usually easily cleared by the Kupffer Macrophages in the Liver and not usually pathogenic.

Small immune complexes: are not effectively cleared, and thus circulate longer, having more time to precipitate in their pathologic locations.

Negatively charged complexes: Tend to bind to endothelium and basement membrane, causing vasculitis.

Question 5

A/27. Type III-IV. hypersensitivity reactions. Clinical and pathologic manifestations

What are the clinical diseases caused by type 3 hypersensitivity reactions? What are the antigens involved?

Answer 5

Vasculitis, Glomerulonephritis, and Arthritis are the main features of most diseases.

Local immune complex disease pathology is mimicked by the Arthus reaction. You injuect antigen into the skin of a previously immunized animal. Immune complex formation at the injection site demonstrates the same characteristics as many immune complex diseases. Over 4-10 hours, the injection develops edema, bleeding, and occaisionally ulceration.

Diseases:

1. Systemic Lupus Erythematosus: Nuclear antigens
2. Post-streptococcal glomerulonephritis: Streptococcal cell wall antigens
3. Polyarteritis nodosa: Hepatitis B virus antigens
4. Reactive Arthritis: Bacterial antigens- Yersinia
5. Acute Serum Sickness: Many proteins of foreign animal’s serum used for passive immunization, for snakebite antivenom (used to be)

Question 6

A/27. Type III-IV. hypersensitivity reactions. Clinical and pathologic manifestations

What are type 4 HS reactions?

What is the immune cell basis of them?

Answer 6

Type 4, aka T-cell mediated hypersensitivity reactions.

Two main types:

1. T-cell Mediated Cytotoxicity
2. Delayed-type Hypersensitivity.

Delayed type hypersensitivity: T-h mediated.

Naive CD4+ T lymphocytes recognize peptide antigens of self or microbial proteins in association with class II MHC on APCs

If the DCs produce IL-12, the naive T cells differentiate into effector
cells of the TH1 type.

If the APCs produce IL-1, IL-6, or IL-23 instead of IL-12,
the CD4+ cells develop into TH17 effectors.

On subsequent exposure to the antigen, after about 6-12 hours, the previously generated effector cells are recruited to the site of the antigen, and activated by the antigen presented by local APCs.

The TH1 cells secrete IFN-γ, which is the most potent macrophage activating cytokine known.
TH17 effector cells secrete IL-17 and several other cytokines,
which promote the recruitment of neutrophils (and monocytes)
and thus induce inflammation, lysosomal damage.

Cell-mediated Cytotoxicity.

CD8+ cytotoxic T-cells and may recognize the antigens presented by MHC-I molecules, and directly kill the cells presenting it.

Question 7

A/27. Type III-IV. hypersensitivity reactions. Clinical and pathologic manifestations

What are the diseases caused by type 4 HS reactions?

Answer 7

1. Rheumatoid arthritis
2. Multiple sclerosis - protein antigens in myelin, myelin basic protein
3. Type 1 diabetes mellitus - several antigens in the beta cells
4. Hashimoto thyroiditis - Thyroglobulin
5. Inflammatory bowel disease - GI flora, GI self antigens
6. Autoimmune myocarditis - Myosin heavy chain protein
7. Contact sensitivity. - oils from within poison ivy.
8. Tubuerculin reaction

Question 8

A/27. Type III-IV. hypersensitivity reactions. Clinical and pathologic manifestations.

What is a major histologic characteristic of Type 4 delayed type hypersensitivity reactions?

Answer 8

Perivascular cuffing, caused by accumulation of T helper cells and macrophages near the vessel, and cytokine/vasodilator secretion creating a local edema and fibrin deposition around the vessel.

A ring of leukocytes around the outside of a vessel, with another border of fluid around these cells.

Question 9

A/28. Pathology of transplantation

General causes of transplant rejection

Answer 9

Allografts: transplant from one person to another person.

Rejection: Usually because of the differences in MHC molecules.

MHC-1 molecules presenting graft-intracellular antigens is recognized as a foreign intracellular antigen being presented by CD8+ T cells, which are directly cytotoxic to the graft cells.

Antigen presenting cells of the host or the graft will pick up cell debris from dying cells of the graft (which will invariably occur due to both the surgery and due to cytotoxic T cell response), and present the graft peptides as foreign extracellular peptides with MHC 2 molecules. This activates T helper cells against graft material, which induce both a Delayed type hypersensitivity T-cell reaction as well as a B-cell antibody reaction against the graft material.

Question 10

A/28. Pathology of transplantation

What are the categories of transplant rejection?

Describe Hyperacute rejection

Answer 10

1. Hyperacute rejection
2. Acute rejection
3. Acute Cellular rejection
4. Acute Humoral rejection
5. Chronic rejection.

Hyperacute rejection: Occurs immediately, within minutes or a few hours after transplantation. The tissue will rapidly become cyanotic, with discolored patches, and nonfunctional.

Histology: Throughout the tissue there is acute arteritis and arterioloitis, thrombosis, and ischemic necrosis. Virtually all arteries will have acute fibrinoid necrosis, causing stenosis or complete occlusion.

It is caused by pre-formed, circulating antibodies, which immediately bind to antigens on the endothelial cells.

Good HLA-geneotype matching has made hyperacute rejection relatively rare <0.5%.

Question 11

A/28. Pathology of transplantation

Describe Acute Rejection.

Answer 11

Acute rejection:

1. Occurs due to an adaptive immune response.
   
   • In non-immunosuppressed patients, it takes a few days to weeks to develop.
   • In immunosuppressed patients, it can take months or years to develop.
2. Involves components of both cellular and humoral based immunity.

Acute cellular rejection:

• Cytotoxic T cells and Helper T cells infiltrate the tissue.
• There is edema and mild hemorrhage into the interstitium.
• There is also lots of mononuclear/macrophage infiltration.
• Endothelitis
• Focal tubular necrosis in the kidney
• Hyaline arteriosclerosis in the glomerulus

Acute humoral rejection:

• Based on antibodies against graft antigens, formed after transplantation
• Vasculitis and vascular necrosis
• Neutrophil infiltration
• Thrombosis
• Fibrosis, fibroblasts, fibromyocytes
• Foam cells
• Hyperplastic arteriolosclerosis
• Complement system binding of the antibodies and complent induces reactions.
• Complement system metabolic products are deposited into the graft, and histochemical staining of C4d is used to identify antibody-mediated graft r ejection.

Question 12

A/28. Pathology of transplantation

Chronic rejection

Answer 12

Chronic rejection:

1. Occurs over months/years
2. Progressive failure of the organ (in kidney grafts, shown by progressive increase in creatinine)
3. Chronic vascular damage causes intimal hyperplasia of the arteries and arterioles, and increased ECM synthesis.
4. Decreased perfusion, and organ ischemia.
5. Parenchyma becomes fibrotic.

Question 13

A/28. Pathology of transplantation

What are the methods of increasing graft survival?

Answer 13

1. Good HLA matching.
2. Immunosuppressive drugs.
3. Attempts to induce a T-reg response/immune tolerance to the graft, by graft exposure in the presence of B7 inhibitors or other inhibitors of the T-cell co-stimulator molecules. Binding of the B7 of an APC to CTLA-4 of T-cells causes inhibition of the activity of T-cells.

Chronic immunosuppression has major side effects:

1. Increased infections
2. Increased risk of virus-mediated cancers
   
   • EBV-induced lymphomas, nasopharyngeal carcinoma and EBV-associated gastric carcinoma
   • HPV-induced squamous cell carcinomas
   • Kaposi sarcoma, KS-associated herpes simplex virus

Question 14

A/28. Pathology of transplantation

Transplantation of HSCs

Answer 14

HSC transplants are given for hematopoietic malignancies.

Sources:

1. bone marrow donors,
2. peripheral blood after stimulation with growth factors,
3. umbilical cord.

HSC rejection is mediated by host T cells and NK cells.

In HSC transplantation, graft vs. host disease can occur.

Question 15

A/28. Pathology of transplantation

graft vs host disease

Answer 15

Occurs after transplantation of:

1. HSCs
2. Lymphocyte rich organs, such as the liver,
3. Large transfusion of non-irradiated blood.

Acute GVHD

• Occurs days to weeks after transplant
• Epethelial cell necrosis in the skin, gut, liver (hepatocytes form an epithelium)
• Bile duct destruction causes jaundice
• Mucosal ulceration in the gut causes bloody diarrhea
• Skin epithelial damage causes generalized rash

Chronic GVHD

• Skin leasions develop that look like systemic sclerosis,
  
  • Subcutaneous collagen dposits and hardened skin.
  • Dry or wet gangrene of the extermities.
  • Ulcers
  • Eventual fingernail degeneration/resorption
  • vasospasm causing white cold skin spots

Question 16

A/29. Pathomechanisms of autoimmune diseases

General causes of autoimmunity, and potential triggering events developing self-reactivity.

Answer 16

Autoimmunity: Immune reactions to self‐antigens. May be to a specific organ/tissue, or may cause systemic problems.

Central tolerance

Peripheral tolerance

Autoimmunity arises due to a break down in the self-tolerance

From a combination of inherited susceptibility genes (high twin inheritance, more prevalent in women), along with an environmental trigger that alters the display of self-antigens.

Potential triggers:

1. Infection and molecular mimicry.
2. Tissue injury and apc bystander uptake. Exposure to a foreign antigen with molecular similarity to a self antigen, along with costimulatory activating signals.
3. UV radiation causing cell death and exposure of nuclear antigens
4. Smoking and chemical modification of self antigens, post transcriptional reaction with toxins, altering self antigens, rendering them immunogenic.

Question 17

A/30. Systemic lupus erythematosus, Rheumatoid arthritis

SLE: What are the main cellular/molecular mediators of SLE pathology?

What are the most at-risk groups of people for SLE?

Answer 17

SLE is mainly antibody mediated, due to a fundamental failure of self tolerance, producing many different reactive self antibodies.

1. anti-Nuclear abs
2. anti-RBC
3. anti-lymphocyte
4. anti-platelet
5. anti-phosphollipid

It is higher in women than men, and higher still in black american women than white women. Its onset is usually in the 20s or 30s.

Question 18

A/30. Systemic lupus erythematosus, Rheumatoid arthritis

SLE: what are the probably factors causing the generation of anti-nuclear antibodies

Answer 18

1. Some kind of defective clearance of nuclear antigens after cell apoptosis, causing slight elevation of nuclear antigens present
2. Failure of T and B cell tolerance to these antigens.

Question 19

A/30. Systemic lupus erythematosus, Rheumatoid arthritis

SLE: what are the major mediators of injury

Answer 19

Immune complexes, anti-blood cell antibodies, and anti-phospholipid antibodies.

1. Immune complexes.
   
   • A​​nti-nuclear antibody binds DNA or DNA/protein complexes. Forms LE-bodies (the term for this immune complex). LE bodies are taken up by macrophages, and LE-filled macrophages are seen in SLE histology.

• Deposition on endothelial cells: acutely; Necrotizing vasculitis. chronically; Fibrosis and luminal obstruction.
• Arteriolosclerosis.
• Deposition onto the glomerular filtration membrane, attracts a general immune response, causing glomerulonephritis, and eventual destruction of the membrane/glomerulus.
  
  • Causes major proteinuria, which then subsequently cuases nephrotic syndrome, hyaline deposition in the renal tubules, and severe renal insufficiency/proteinuria, renal failure.

1. Antibody-mediated cell cytotoxicity against RBCs, WBCs, and platelets.
2. Anti-phospholipid antibody mediated membrane damage, along with the blood cell destruction, increases circulating phospholipids (thromboplastin) causing frequent thrombosis, capillary blockage.

Question 20

A/30. Systemic lupus erythematosus, Rheumatoid arthritis

What are the diagnostic criteria for SLE

Answer 20

Diagnostic criteria, there needs to be at least 4 of the following:

1. Butterfly rash
2. Discoid rash
3. Photosensitivity induced rash
4. Oral mucosa ulcers
5. Arthritis in more than one peripheral joint
6. Serositis: Pleuritis or pericarditis
7. Renal problems: protein or cells in the urine.
8. Neurology disorders - Seizures, physchosis
9. Any hemolytic loss of blood cells, anemia, leukopenia,
10. Presense of self-reactive antibodies

Question 21

A/30. Systemic lupus erythematosus, Rheumatoid arthritis

What are the clinical types of SLE, with relation to the kidney?

Answer 21

There are 6 patterns of renal disease in SLE patients. Kidney problems are the biggest concern.

1. Class I. Minimal Mesangial Lupus Nephritis.
2. Class II. Proliferative Mesangial LM.
3. Class III. Focal LM
4. Class IV. Diffuse LM
5. Class V. Membranous LM.
6. Class VI. Advanced Sclerosing LM

• Class I. Minimal Mesangial Lupus Nephritis. rare
  
  • No big problems, complex deposition in the mesangial cells of the glomerulus (cells outside of the capillaries, kind of structural cells)
• Class II. Mesangial Proliferative Lupus Nephritis.
  
  • 10-25% of cases. Mild clinical symptoms
  • Mesangial deposition of complexes causes mesangial proliferation and moderate fibrosis
• Class III. Focal Lupus Nephritis
  
  • 20-35%
  • Half fo the glomeruli are lesioned.
  • Swelling and proliferation of the endothelium and mesangium
  • Neutrophil infiltration
  • Fibrinoid necrosis
  • Capillary thrombi
  • Causes mild hematuria and proteinuria, with some RBC casts and renal insufficiency.
• Class IV. Diffuse Lupus Nephritis
  
  • ​35-60%
  • Causes the most serious lesions and renal failure
  • more than half of the glomeruli
  • Endothelial and mesangial proliferation. The proliferation may be so extensive, that the cells move into the bowmans space, forming glomerular crescents.
  • Extensive fibrinoid thickening of the subendothelium within the glomerulus causes wire loop fibrinoid necrosis. Which can completely fill/obstruct the glomerular capillary.
  • Clinical: hematuria, proteinuria, hypertension, and renal insufficiency.
  • Eventually causes glomerulosclerosis/scarring.
• Class V. Membranous Lupus Nephritis.
  
  • ​10-15%
  • Widespread thickening of the glomerulus capillary basement membrane.
  • Causes severe proteinuria and over nephrotic syndrome.
• Class VI. Advanced sclerosing lupus nephritis
  
  • Complete sclerosis of more than 90% of the glomeruli.
  • aka. End Stage Kidney Disease.

Question 22

A/30. Systemic lupus erythematosus, Rheumatoid arthritis

What are the non-kidney related disorders associated with SLE?

Answer 22

Skin:

• Erythematous butterfly rash,
• Measle-like discoid rash on the face or body
• Photosensitivity of the rashes
• Edema of the dermis
• Mononuclear infiltration around the blood vessels of the skin

Joints:

• Arthritis, swelling
• Mononuclear cell infiltration in the synovial membrane
• Generally does not destroy or damage the cartilage ro bones

Nervous System:

• Focal neurological defecits due to ischemia of different regions. Memory/cognitive deficits.
• Seizures
• Microinfarcts, transient ischemic attacks from the pro-coagulative state of SLE.

Spleen:

• Splenomegaly
• Follicular hyperplasia
• Thickening and perivascular fibrosis of the central arteries.

Serosal Membranes:

• Pericardial effusions
• Pleural effusions

Heart:

• Pericarditis,
• Pericardial effusion
• Myocarditis,
• Endocarditis and valve lesions
• Verrucous nonbacterial endocarditis lesions.
• Coronary artery disease
• *

Question 23

A/30. Systemic lupus erythematosus, Rheumatoid arthritis

Rheumatoid Arthritis. General description, and common autoantibodies, and etiology

Answer 23

• Systemic autoimmune inflammation.
• Causes a proliferative, non-purulent synovitis.
• Progressively destroys the articular cartilage and bone.
• May also progress to involve the skin, blood vessels, heart, muscles, and lungs.

Rheumatoid arthritis is predominantly a T-cell mediated disease (not immune complex), but autoantibodies are also produced in some but not all patients. They are:

• Cyclic citrulinnated peptides, citrulinated-fibrinogen,
• type 2 collagen
• alpha enolase
• vimentin

About 50% of the risk for RA is attributed to be genetic, due to HLA allele polymorphism.

Other potential triggering factors are inflammation, and smoking, which can promote the citrullination of proteins. The abnormal citrulinnation may change a normal self protein into an immunogenic one.

Question 24

A/30. Systemic lupus erythematosus, Rheumatoid arthritis

What is Rheumatoid factor.

Answer 24

Rhematoid factor: IgM autoantibodies (sometimes IgA) that bind to the Fc regions of self IgG.

These antibodies form immune complexes that can deposit. Although the role of rhematoid factor in pathology is not clear, it can be a diagnostic factor.

Question 25

A/30. Systemic lupus erythematosus, Rheumatoid arthritis

General pathogenesis of RA, and clinical presentation.

Answer 25

Primarily T cell mediated disease, Th1 cells and Th17 cells, recruiting B cells, macrophages, and other leukocytes to the inflamed synovial tissue, causing immune mediated damage, collagenases, elastases, increasing osteoclast activity.

Clinical presentation:

• Symmetric arthritis of the hand, feet, arm and leg joints.
• Chronic papillary synovitis of these joints
  
  • ​Inflammatory cell infiltration to the joints, and lymphoid tissue nodule (papule) formation.
  • Pannus formation from the synovial hyperplasia- excessive growth and proliferation of the synovial membrane, forming folds and layers within the joint.
  • Angiogenesis within the joints.
  • Increased osteoclast activity and bone erosion.
  • Joint fibrous ankylosis - stiffening due to the fibrous adhesions of the inflamed synovium
  • Tendon and ligament destruction causes the postural abnormalities of the joints - Radial deviation of the hands, ulnar deviation of the fingers.
• Subcutaneous Rheumatoid nodules form on the skin of the arms
• In its severe stage, extra-articular symptoms occur:
  
  • ​Vasculitis
    
    • ​Raynaud’s vasospasm of the fingers.
    • Vascular amyloidosis.
  • Pleuritis
  • Pericarditis
  • Lung fibrosis

Question 26

A/31. Sjögren’s syndrome, Scleroderma, Polyarteritis nodosa

Scleroderma

Answer 26

aka Systemic Sclerosis. Disroder causing extensive fibrosis in multiple tissues. It is called scleroderma, because the skin is the main target, but lesions occur throughout the body.
The skin problems are the most obvious feature, but the GI, lungs, kidneys, heart, and skeletal muscle cause the morbitiy and mortality.

It typically begins in the face, and progresses down and outward.

It is divided into limited or diffuse scleroderma.

Limited: Mild skin lesions, limited to the fingers and face. Limited scleroderma is often called CREST syndrome

• Calcinosis - soft tissue calcium deposits
• Raynauld phenomenon - vasospasm of the digits
• Esophageal motor impairment - reflux, and decreased esophageal motility, dysphagis
• Sclerodactily - thickening of the skin at the fingers and toes
• Telangiectasia - capillary dilation causing clusters of red dots on the skin, which sometimes may elucidate the whole capillary bed like a spider web.

Diffuse: Widespread skin involvment, rapidly progressing to visceral problems.

• GI sclerosis: decreased motility and absorption, malabsorption syndrome
• Lung fibrosis: Honeycomb lung seen on CT or post-mortem. Cor pulmonale
• Kidney fibrosis: Renal sclerosis, hypertension, renal ischemia, damage
• Joints: Cause Reumatoid Arthritis-like symptoms.

Antibodies:

• anti-Topoisomerase abs
• anti-Centromere abs

Question 27

A/31. Sjögren’s syndrome, Scleroderma, Polyarteritis nodosa

Sjogren’s syndrome

Answer 27

Sicca Syndrome, aka Sjogren Syndrome.

Autoimmune T-cell reaction against the cells of the Lacrimal and Salivatory glands.

Dry mouth, causes oportunistic Candida infections on the tongue, fancy name = xerastoma

And Dry eyes, causing conjunctivitis in the eyes. fancy name = keratoconjunctivitis

Less frequently, it can affect Bronchial glands, Nasal glands, Vaginal glands

Anti-Nuclear antibodies have been seen.

Question 28

A/31. Sjögren’s syndrome, Scleroderma, Polyarteritis nodosa

Polyarteritis nodosa

Answer 28

Polyarteritis Nodosa (PAN) Necrotizing vasculitis of the walls of medium** and **small** sized **muscular arteries. Which presents in segmented, transmural, necrotic, inflammed nodes along the vessel.

The necrotic region just involves a segment of the vessel, like a necrotic peice of pie.

Consequences:

• Typically affecting the kidney and GI tract.
• vessels are prone to aneurysm, rupture
• eventual fibrosis of the vessels leads to organ ischemia, ulceration, infarcts.
• Hypertension from renal fibrosis
• Abdominal pain or bloody stool from GI ulcers
• Occurs in young adults, and presents as a remitting-relapsing disease.
• Is fatal if untreated, but can be kept in remission by immunosuppressants for a long time very effectively in 90% of people.

Caused by immune complex deposition.

1. 30% are caused by immune complexes of Hepatitis B surface antigen and its antibody.
2. The remaining are idiopathic.

Question 29

A/32. Primary and secundary immune deficiency diseases (except AIDS)

Primary immune deficiencies

Answer 29

• X-linked Agammaglobulinemia (XLA)
  
  • Pre-B cells don’t differentiate to B cells.
  • B cell maturation stops after heavy chain re-arrangement
  • No Ig Light Chain is ever produced
  • recurrent bacterial infections: S. aureus. Streptococcus pneumoiae
  • X-linked, so more common in males
  • Symptoms apparent within 6 months of birth
• Common variable immunodeficiency
  
  • hypo-production of IgG antibodies due to no Plasma cell differentiation.
  • Chronic bacterial infections
  • Equal among males and females
  • Doesn’t get diagnosed until 20-30 years
  • Normal number of mature B cells, but no plasma cells
• Isolated IgA deficiency
  
  • ​failure of IgA class switching
  • Recurrent Mucosal infections, brochial, GI tract.
• Hyper IgM syndrome
  
  • ​Total failure of class switching
  • Only IgM antibodies are made.
  • Often due to a T-helper cell impairment, of the CD40Ligand costimulator molecule
  • Impaired opsonization of everything, chronic bacterial infection
• Thymic hypoplasia, DiGeorge Syndrome
  
  • ​Chromosomal deletion causes pharyngeal pouch developmental malformation
  • Lack ot T-cell immunity
  • Intracellular bacteria, viruses, tumors
• SCID. Severe Combined Immunodeficiency
  
  • ​Caused by many different genetic defects. RAG recombinase mutations are a classic example, as is Adenosine Deaminase and dATP addumulation in rapidly dividing cells.
  • Common feature is a severe defect of both T and B cells, OR a severe defect of T cells which also prevents their activation of the B cell response.
  • about half are X-linked
  • half are autosomal recessive.
  • Thymus is very underdeveloped
  • Lymph nodes and Lymphoid tissues are atrophic, have no Germinal Centers, and no Paracortical T cells.
  • Severe infections of all kinds chronically occur, and are usually lethal at a young age. Bone marrow transplant is the only treatment.
• Lymphocyte activation defects
  
  • ​Defects in T-helper cell differentiation, activation of the inflammatory response
• Wiskott-Aldrich syndrome, Immune deficiency with thrombocytopenia and eczema.
  
  • ​X-linked recessive disease with eczema and thrombocytopenia
  • Progressive age-related depletion of T-cells.
  • Loss of cellular immunity.
  • Loss of B cell activation
  • Recurrent infections and early death
• Complement deficiencies
  
  • ​C3 deficiency - bacterial infections
  • C1q, C2, C4 deficiency (opsonization deficiency) - immune complex disease
  • C5-C8 deficiency - recurrent Neisseria infections
  • C1 inhibitor deficiency - Hereditary Angioedema
• Phagocytes
  
  • ​MPO defect - chronic granulomatous diseases
  • Integrin, cell adhesion molecule defect - Leukocyte adhesion deficiency

Question 30

A/32. Primary and secondary immune deficiency diseases (except AIDS)

Secondary immune deficiencies

Answer 30

Secondary immune deficiency

a) These are immune deficiencies secondary to other diseases / therpaies
b) Much more common than primary immune deficiencies
c) Seen with patients that have: malnutrition, infection, cancer, renal disease, sarcoidosis
i. Most common cause: therapy‐induced immune suppression of bone marrow / lymphocytes
d) AIDS is the most important secondary immune deficiency disease: AIDS (see topic A/33)

Question 31

A/33. AIDS

mechanism of infection,

epidemiology, transmission

structure

Answer 31

• HIV virus retroviral disease
• Depletes CD4+ T helper cells.
• The CD4 molecule on T-cells is a high affinity HIV receptor, which is how it enters.
• Certain strains then use the CXCR4 receptor and others use the CCR5 receptor as a co-receptor for entering.

epidemiology

• Homosexual males
• heterosexual sex, easier to transmit to women
• IV drug abuse
• Blood transfusion recipients, in previous years.
• Hemopheliacs who get lots of coagulant factor transfusion in previous years.

Transmission

• Sex or direct blood blood contact
• Congenital transmission

Structure

• Core protein:
  
  • Major capsid protein
  • Nucleocapsid protein
• 2 Genomic RNA copies
• 3 Viral enzymes
  
  • Protease
  • Reverse transcriptase
  • Integrase​
• Matrix protein
• Virion envelope proteins
  
  • glycoproteins, gp120, gp41, essential for HIV infection and T-cell binding.
• Genes: GAG, POL, ENV

Question 32

A/33. AIDS

Cell entry

Pathogenesis

Answer 32

1. gp120 binds to CD4
2. gp120 has a conformational change
3. gp120 binds its chemokine co-receptor
4. gp41 penetrates the membrane
5. Virus core enters the cytoplasm
6. Viral reverse transcriptase generates cDNA from the retroviral RNA genome.
7. cDNA is integrated into host genome.

Remains latent and non-transcribed, or enters the lytic phase and virus is transcribed and completed.

Question 33

A/33. AIDS

Disease progression, associated diseases

Answer 33

Acute stage:

1. dendritic cells take up the virus at the site of infection/exposure
2. DC’s move to lymph node
3. Virus is transmitted from DCs to T cells
4. Virus replicates in lymph node
5. Viremia, circulating virus in the infected T-cells and free virus circulating.
6. Infection spreads to macrophages, T-cells, and DC cells in the peripheral lymph tissue
7. Immune response decreases the free virus, reducing viremia amount

Chronic stage, clinical latency period

1. Spleen and Lymph node are the major reservoirs of virus replication and harboring.
2. During the initial latency period, the body is still capable of producing new T cells.
3. Destruction of T cells occurs more progressively over several years.
4. progressive destruction of the CD4+ T cell population shifts the ratio of CD4+/CD8+ cells from its normal ratio of 1-2, down to less than 0.5.
5. This low of a ratio is a common finding in AIDS, and the depletion of T helper cell immune activation is the hallmark of AIDS.

Latent HIV can reside in long-life memory T cells for their entire lifespan, and then upon their activation by another type of infection, the lytic cycle of the virus begins, and more virus is produced, re-inficting more local CD4+ cells, Monocytes, and Macrophages.

Question 34

A/33. AIDS

Clinical pathogenesis of AIDS

Answer 34

Acute phase: 3-6 weeks after infection

• 50-70% of infected people will have a flu-like illness, with sore throat, muscle pain, fever, rash, and sometimes aseptic meningitis, which resolves on its own.
• Virus is being highly produced during this phase, and there is high viremia, which seeds the virus into the perpheral lymphoid tissues.
• There is a mild reduction in CD4+ T cells.
• A virus-specific immune response then develops, generating virus-specific CD8+ cytotoxic T cells.
• After the viremia in the blood abates, CD4+ cells return to normal.

Chronic phase lasts for several years after infection

• Virus is continually replicating in the peripheral lymphoid tissue
• Minor opportunistic infections may occur, such as Candida.
• Progressive decline in total CD4+ cells.
• Progressive increase in the percentage of CD4+ cells infected with HIV.

Crisis phase:

• Persistent lymphadenopathy (lymph node swelling) concurrent with persitent rash, fatigue, fever, marks the onset of crisis phase.
• Their is a catastrophic failure of the host defense, and marked viremia returns.
• Causing persistent fever >1 month, fatigue, weight loss, diarrhea.
• AIDS Dementia Complex and other neuropathies become evident.
• CD4+ cells are very low.
• Serious opportunistic infections begin, which are 80% of the mortality.

Question 35

A/33. AIDS

Opportunistic infections and other consequences of AIDS, during the crisis phase.

Answer 35

Major opportunistic infections.

1. Pneumonia
2. Protozoan and Helminths
3. Fungal, Candida
4. Atypical bacteria
5. Tuberculosis

Neoplasms - virus generated neoplasms.

1. Kaposi Sarcoma, a HSV-strain induced cancer of mesenchymal origin. Fomrs the typical red patches on the skin, but can also cause them on the gums or other mucosal surfaces
2. Non-hodgkin lymphomas, often in the brain
3. Cervical carcinoma, from HPV.

Central Nervous System Involvement - 90% of AIDs patients have a neurologic pathology at autopsy

1. Some type of evident neurologic dysfunction (motor/cognitive)
2. Aseptic meningitis - from the HIV itself.
3. Vaculolar myelopathy
4. Peripheral neuropathy
5. Progressive Echephalopathy, known as the AIDS dementia complex.
   
   1. ​progressive dementia
   2. peripheral neuropathies, muscle disorders, sensory disorders