Signal 1:TCR, CD4 (or 8)

Signal 2: CD28

MHC II

Helper/inducer - secretes cytokines to signal other cells

MHC I

Cytotoxic/suppressor - directly kills infected cells

B cell receptor complex

Signal 1: Membrane bound IgG/IgM + Antigen

Signal 2: CD21

Can lyse a tumor cell or viral infected cell WITHOUT PREVIOUS SENSITIZATION

Occurs because virus and tumor cells decrease self MHC molecules, which are NK inhibitory, leading to destruction of these cells

CD16+ - an Fc receptor that allows for binding and lysis of IgG coated target cells

CD56+

Chromosome 6 

Class I MHC Cluster = HLA-A, HLA-B, HLA-C; binds CD8 cells

Class II MHC Cluster = HLA-DP, HLA-DQ, HLA-DR; binds CD4

Class III MHC Cluster = Complement

Ankylosing Spondylitis

HLA-B27

Immediate Hypersensitivity

Disorders: Anaphylaxis; allergies; bronchial asthma

Mechanism: TH2 cells bind B cells, causing IgE secretion,  which binds mast cells and causes release of vasoactive amines, and other mediators; Inflammatory cells are eventually recruited

Benefit: Helminth infections

Quick Notes: Allergen, IgE, Mast Cells bound to allergen, compound come out and cause immediate reaction and late phase reaction (hours later) when eosinophils may be present; ALL LOCALIZED

Antibody Mediated Hypersensitivity

Disorders: Transfusion rxn, 

3 Mechanisms: 1) Opsonization and phagocytosis

2) Complement and Fc receptor mediated inflammation (glomerulonephritis and vascular rejection of grafts)

3) Antibody-mediated cellular dysfunction (myasthenia gravis)

Immune Complex Mediated Hypersensitivity

Systemic Lupus Erythematosis

2 Types of antigens: exogenous and endogenous

3 Phases: Immune complex formation, deposition (kidney or joints) and inflammatory reaction (C3a, C5a and Fc rec. binding on macrophages and PMNs)

2 types of disease: cirulating immune complex's or in situ immune complex's

Cell Mediated Hypersensitivity

2 types: based on T cell,

CD4 = delayed type hypersensitivity

CD8 = direct cell cytotoxicity (graft rejection)

Examples: Tuburculin Skin Test; Poison Ivy, looks like type I BUT IS TYPE IV

a.     Host T cells directly recognize the  MHC on graft cells

b.     Host CD4 Th cells are triggered to proliferate and secrete cytokines via recognition to donor MHC2

Host CD8 recognise MHC1 and differentiate into CTLs, KILL CELLS IN GRAFT

A special form of antibody mediated rejection where the recipient has preformed antibodies; leads to ischemic death of the graft

i.e. multiparous women and pt who receives many blood transfusions

1) Cells that inhibit T cell mediated immunity

2)  Monoclonal antibodies

3) Downside is vulnerability to fungal, bacterial, viral infections and EBV induced lymphoid tumors

a.     Autoimmune reaction must be present

b.     Evidence that reaction is NOT secondary to tissue damage

c.     Absence of another well defined cause of the disease

• Clonal Deletion (deletion of auto-reactive cells)
• Clonal anergy (inactivity)
• Peripheral suppression by T cells; Some CD8 cells can inactivate T helper cells and B cells

Diagnostic 

-DS DNA

-Smith (Sm) antigen

Others

Abs against hematopoietic cells (RBCs, platelets, lymphocytes)

Antiphospholipids: false + syphilis test, procoagulation TROUBLE

Type III (Immune complexes)  are associated with most visceral lesions i.e. DNA anti DNA complexes detected in glomeruli, low levels of serum complement and granular deposits of Ig, complement in glomerulus

Type II (antibody mediated) - antibodies against RBCs, WBCs and platelets

Xerostomia (dry mouth) and keratoconjunctivitis (dry eye) from destruction of salivary and lacrimal glands

ANAs: Anti-SS-A and Anti-SS-B

Typically female over 40

Complication: B-CELL LYMPHOMA!!! RARE BUT SERIOUS; also connective tissue diseases or pseudolymphoma

Presentation: drawn mask face, chronic ischemia of fingers, won't be able to swallow

Major Organs/Pathologic findings: Skin – chronic ischemia with traumatic ulcerations may lead to autoamputation of fingers; face appears as drawn mask: GI – atrophy, fibrosis of esophageal wall, lower 2/3; vessels show thick walls

ANA: Scl-70, directed against DNA topoisomerase I; anticentromere antibody

Patient: Women 3rd-5th decades of life (20-40 y/o)

Limited scleroderma

Limited skin involvement, fingers, face, visceral involvement late

Disorders: dermatomyositis, polymyositis, inclusion body myositis

ANA: Jo-1 ab against t-RNA synthetase

Causes inflammation of the muscle

Pts have features of SLE, inflammatory myopathy and SS; LACK renal disease

ANA = U1RNP, antibody to ribonucleoprotein

Virus is carried in semen w/in mononuclear cells and in cell free fluid

Through abrasions in rectal, oral or vaginal mucosa -> direct inoculation into blood

 Via direct contact with mucosal cells: taken up into dendritic cells or CD4+ cells within mucosa

Risk Factors: Another STD (ulcerative diseases including syphilis, chancroid, herpes: produce ulcers)(Chlamydia, gonhorrhea: because infection increases lymphocytes and lymphocytes are what is infected); Uncircumsized male

Viral core:

 Capsid protein, p24 is the most readily detected antigen

   Nucleocapsid protein p7/p9

Genomic RNA, two copies

Three enzymes: protease; reverse transcriptase and integrase

Matrix protein p17

Envelope: glycoproteins gp120; gp41

Pol products include enzymes

Gag products include capsid protein p24

rev, vif, nef, vpr, vpu and tat

Tat (transactivator) gene product increases viral replication

Cells infected: T cells, macrophages, dendritic cells

CD4 is the receptor for HIV

Mechanism: 

Gp 120 binds CD4 causing a conformational change

 Gp 120+CD4 bind CCR-5 (chemokine coreceptor)

Gp41 membrane perforation and fusion

HIV RNA genome transcribed into proviral DNA by reverse transcriptase

Proviral DNA is integrated into host genome by integrase

 HIV virions assembled via protease

HIV virions released via budding

Receptor for HIV

Homozygous mutation = NO AIDS (R5 type)

Heterozygous mutation = DELAYED AIDS

Lymphopenia – predominantly caused b yselective loss of CD4 helpter T cell subset

Decreased T-cell function in vivo: 1) Decreased T-cell function in vivo 2) Susceptibilty to opportunistic infections 3) Susceptibility to neoplasms 4) Decreased delayed type hypersensitivity

Altered T cell function in vitro: Decreased IL-2 and IFN-y production

Polyclonal B-cell activation: 1) Hypergammaglobulinemia and circulating immune complexes 2)  Altered monocyte or macrophage functions

]Macrophages – Macrophages in tissue = HIV reservoirs; Disseminate infection through the body

·      Follicular dendritic cells (germinal centers of LNs) = reservoir for HIV, trap virus particles on cell surface

·      CNS is a major target of HIV; HIV is carried to the brain via infected monocytes; CNS macrophages and microglia become infected, fuse and form giant cells

Infected mucosal memory T cells drain to lymph nodes and spleen

Virus is at low/nondetectable levels in blood; viral replication occurs in lymphoid tissues

Infection of lymphoid tissue leads to massive CD4 cell loss

 Leads to viremia and clinical acute retroviral syndrome

Partial control of viral replication occurs, leading to clinical latency

OTHER INFECTION causes extensive viral replication and CD4 lysis, destruction of lymphoid tissue and depletion of CD4 T cells

• o   Large inoculum i.e. blood transfusion
• o   Older Age at seroconversion
• o   Perinatal HIV
• o   Smoking
• o   High viral load set point; virulent HIV subtype

• o   Asymptomatic over 10 years
• o   Low viral set point, low viremia, stable CD4 counts
• o   CCR5 mutation
• o   GB hepatitis infection
• o   Infection by nef-mutated virus
• o   TH1 dominant response to infection

•   Dramatic increase in viremia
•    Drop in CD4 T lymphocytes
• Fever >1 mont; fatique; weight loss; diarrhea
• HIV infection +1 or more of the following
• Any AIDS indicator diseases i.e. opportunistic infections, AIDS related neoplasms

• 1)   diagnose HIV infection: serology for anti-HIV ½, IgG and IgM, p24; Positive serology must be confirmed with western blot or viral RNA
• 2)   follow course of disease: Viral load and CD4 T lymphocytes are monitored

• o   >500 w/o opportunistic infection = acute
• o   <200 w opportunistic infection = AIDS or AIDS soon

• ·      Wasting syndrome due to HIV = AIDS defining syndrome
• ·      Premature aging: belived to be related to testosterone deficiency
• ·      Gonadal insufficiency is common in males; may occur in females

• ·      Wasting syndrome due to HIV = AIDS defining syndrome
• ·      Premature aging: belived to be related to testosterone deficiency
• Gonadal insufficiency is common in males; may occur in females
• Trimethoprim sulfa is prophylaxis

·      Chorioretinitis in 25% of pts, most common cause of blindness  in pts w/ low CD4

Herpes Zoster - recurrent infections, 2 or more dermatomes involved, lesions may persist for months

Herpes Simplex - herpes esohpagitis, herpes pneumonia, herpes encephalitis typical of HIV infection

• ·      Cytokine response from EBV infection may end intracellular latency
• ·      Causes poyclonal B-cell activation -> polyclonal gammopathy
• ·      Causative factor in HIV related B cell lymphoma
• ·      Causes hairy leukoplakia of the tongue – heralds progression of HIV disease

• fevers, chills, night sweats and anemia;
• BAD PROGNOSIS; frequenty progressive and disseminated in HIV pts.
• people w/ TB should be tested for HIV and vice versa

• ·      Diarrhea causes w/ HIV: microsporidiosis, cryptosporidiosis

• ·      Abscess caused by Toxoplasma gondii, a parasite.
• ·      Demonstrated as cerebral abscess, pneumonia and retinitis

• Lesions: erythematous papules, subcutaneous nodules; also involve liver, spleen and lymph nodes; may contribute to AIDS dementia
• Cause: Bartonella species

• ·      Kaposi Sarcoma (most common)
• ·      Malignant lymphomas
• ·      HPV-associated carcinoma

• ·      Opportunistic infections: JC virus, toxoplasma
• ·      Asepctic meningitis of acute HIV infection
• ·      AIDS related dementia; progressive encephalopathy aka cognitive motor comples
• ·      CNS lymphoma

• Lipodystrophy syndrome: secondary to protease inhibitors
• 1) Fat redistribution i.e. peripheral wasting, central obesity, buffalo hump
• 2) Metabolic dysfunction; glucose tolerance (frank diabetes), increased TAGs, cholesterol
• 3) Shifts risk from dying of infection to dying of CV risk

Genetic Defect: Bruton Tyrosine Kinase (BTK); Defect BTK -> disordered B-cell maturation -> decreased Ig

Clinical: B-cell symptoms (low Ig) after 6 months (passive from mom before)

Labs: Low IgG IgA and IgM; normal WBC; low B cells

Morphology: decreased follicles in appendix, tonsils, peyers patches; risk of autoimmunity

Infections: Pyogenic Bacterial (staph, strep, H. influenza), enterovirus, giardia

Genetic Defect: Congenital, acquired

Clinical Symptoms: B-cell symtoms in 2nd/3rd decade (10-30-y/o) i.e. recurrent sinopulmonary bacterial infections (pyogenic) enterovirus encephalitis, giardia lamblia, diarrhea, recurrent herpes virus;

Risk for autoimmunity, lymphoma and gastric CA

Labs: All Igs low (low IgG, IgA, IgM)

Morphology: Increased follicles -> enlarged lymph nodes, spleen, tonsils and GI

Genetic Defect: Congenital, acquired

Clinical symptoms: B-cell symptoms (recurrent infections) including mucosal infection risk, especially from virus'; Pollen asthma/hayfever

Most are asymptomatic because IgG still present

Risk: autoimmune disease, anaphylactic transfusion (on 2nd transfution from IgA antibodies produced by pt)

Labs: Low IgA

Morphology: Bronchiectasis (sinopulmonary infection, necrotising pulomnary infection)

Genetic defect: X-linked, CD40 and CD40L mutation

Clinical: B-cell symptoms i.e increased pyogenic infections (IgG), increased mucosal infections (IgA)

Risk of pneumocystic jiroveci pneumonia; risk of autoimmune hematologic rxns including anemia, thrombocytopenia and neutropenia

Labs: Increased IgM and IgD; Decreased IgG, IgA, IgE

Genetic defect: partial deletion of chromosome 22q11; defect in development of 3rd/4th pharyngeal pouches

Clinical: Cyanotic at birth (congenital heart defect) i.e. truncus arteriosus (transposition/tetrology of fallot); thymus is absent (low T cell) so T cell symptoms i.e. viral, fungal and protazoal infections; hypocalcemia tetany (no parathyroid glands)

Labs: Low WBCs (T cells), Ig normal

Morphology: Thymus is not seen on X-ray (largest thing on infant x-ray), decreased paracortical lymphs

Genetic Defects: AR-ADA (adenosine deaminase); X-linked cytokine receptor; MHC classII deficiency

Clinical: At birth- Rash-GVH, Rash-diaper; B&T symptoms including sever infections by bacteria, viruses, fungi, protozoa; infection by opportunistic organisms; failure to thrive

Labs: Low WBCs (no T cells), Low Ig (no B cells)

Morphology: no tonsils, no thymus

Genetic defect: Inherited AD-STAT, AR-DOCK8

Clinical: Eczema; boils-staph, respiratory infections

Labs: Increased IgE, Increased eosinophils; IgG and IgA NORMAL

Genetic defect: X-linked WASP (wiskott-aldrich associated protein), a cytoskeletal protein that links membrain receptors -> defectiv signaling

Clinical: Eczema; B infections and progressive loss of T cells

Labs: Low IgM, High IgA, normal IgG, thrombocytopenia

Systemic amyloidosis

aka amyloid light chain amyloidosis; monoclonal immunoglobulin light chain amyloidosis; MOST COMMON

Monoclonal B-cell proliferations Multiple myeloma and others (raccoon eye presentation)

AL (amyloid light chain)

Immunoglobulin light chains, chiefly λ type

Heart, liver, kidneys, spleen

Systemic amyloidosis

Chronic inflammatory conditions (RA, chronic skin popping of narcotics: Infections causes = TB, osteomyelitis, bronchiectasis; lung abscess

AA

SAA

Liver, spleen, kidney, heart

Systemic amyloidosis

Chronic renal failure; AB2m accumulates in pts on long term dialysis

Aβ2 m (Beta 2 microglobulin)

β2-microglobulin

Kidneys, joints (accumulations)

Systemic amyloidosis

Polyneuropathies (accumulated mutant ATTR)

AA

SAA

Systemic, damaging inflammation response to minor trauma (FYI)

Systemic amyloidosis

Senile cardiac amyloidosis: Familial amyloid polyneuropathy

ATTR

Transthyretin (TTR)

Heart (senile cardiac amyloidosis): peripheral nerves (familial amyloid polyneuropathy)

Localized amyloidosis (only one)

Alzheimer disease +/- Alzheimer disease

AB (amyloid beta)

APP (amyloid precursor protein)

Brain

Endocrine amyloidosis

Acal 

Calcitonin

Thyroid

Endocrine amyloidosis

DM II

AIAPP

Islet amyloid peptide

Pancrease (islet tumor)

Endocrine amyloidosis

AANF

Atrial Natriuritic Factor

Heart

Bronchus is obstructed, caused by mucous plug, exudates, tumors (less common), foreign bodies; trapped O2 is reabsorbed

Mediatinal shift TOWARD atelectasis

Mechanical collapse of the lung; something’s pressing from outside the lung, due to accumulations in pleural space i.e. pleural effusion (CHF), hemothorax, pneumothorax, neoplasms

Mediastinal shift AWAY from atelectasis

·    Heavy, wet lungs (gross); congested alveolar septae; fluid in alveoli; alveolar microhemorrhages; hemosiderin laden macrophages (siderophages; HF cells)(stain with prussian blue?)

brown induration of lung, HF cells in alveoli (stain with Prussian blue)

Sepsis

Diffuse pulmonary infections

Gastric aspiration

Mechanical trauma, including head injuries

Patchy, diffuse alveolar damage

HYALINE MEMBRANES!

Clinical features: dyspnea + cough with minimal sputum; pursed lip breathing to prolong expiration (pink puffer); weight loss from pink puffer breathing; increased AP diameter (barrel chest)

Late complications: hypoxemia, cor pulmonale

CENTRIACINAR EMPHYSEMA MEANS SMOKER!

Additional morphology: upper lobes

Pathogenesis: Protease (PMNs)/antiprotease (A1AT, alpha1 antitrypsin) imbalance

Clinical: Pink puffer, hypoxemia, dyspnea, cachexia

Blebs: apical

Usually Genetic

Additional morphology: lower lobes, anterior margin

Pathogenesis: Protease/antiprotease (A1AT) imbalance; decreased A1AT, congenital: PiZZ

Clinical: Pink puffer, dyspnea, hypoxemia, cachexia

Blebs: apical

Additional morphology: Tall, young adult; subpleural

Pathogenesis: usually in smokers but not always

Clinical: pneumothorax, recurrent; asymptomatic to symptomatic

Blebs: yes

Pathogenesis: scarring with age

Clinical: Asymptomatic to symptomatic

Blebs: yes or no

Additional morphology: No lung damage

Pathogenesis: Follows ressection of lung

No clinical

Blebs: No

Additional morphology: In subcutaneous tissue; head/arms

Pathogenesis: Trauma; coughing w/ bronchile obstruction

Clinical: "crepitance"; swelling; resorbs

Blebs: NO 

"Blue Bloater"

Clinical features: Productive cough, Cyanosis: increased PaCO2, decreased PaO2

·      Increase thickness in mucin glands relative to the overall bronchial wall thickness; due to smoking (increased Reid index) to >50% of lamina propria (normal is <40%); OVER PRODUCTION OF MUCUS

May have mucus casts and lymphocyte infiltrate

• Atopic (extrinsic) – type I hypersensitivity, induced by exposure ot extrinsic antigen
• Intrinsic (nonatopic) – rhinovirus, parainfluenza virus, others lower threshold of vagal receptors to irritants
•  Aspirin induced – due to COX inhibiton w/o affecting lipooxygenase; nasal polyps
• Occupational exposure: type I reaction to fumes, dust
• Allergic bronchopulmonary aspergillosis – bronchial colonization by aspergillus

Allergen induce C TH2 phenotype in CD4+ T cells in genetically susceptible individuals

 TH2 cells secrete: IL-4 – allows plasma cells to class switch to IgE: IL-5 – calls eosinophils: IL-10 – Stimulates TH2 inhibit TH1 helper T cells

Bridging of surface IgE on mast cells, activating the mast cell; Mast cells then release preformed histamine granules causing histamine induce vasodilation in arterioles and histamine induced increases vascular permeability in post capillary venules

Dyspnea and wheezing

Productive cough: cursschmann spirals mixed with charcot-leyden crystals

Severe, unrelenting attack can result in status asthmaticus and death

IL13: Gene cluster for cytokine regulation and IL-4
ADAM-33 polymorphisms – MMP; accelerates proliferation in bronchial wall
Eosinophils
Smooth muscle hypertrophy
Everything else is indistinguishable from chronic bronchitis

Chronic necrotizing inflammation (infection) of the bronchus and bronchioles leading to or associated with permanent abnormal dilation of airway

Due to 1)Bronchiole obstruction leads to resorption atelectasis 2) Necrosis of bronchial wall secondary to inflammation favors retention of secretions; either may occur first

Causes: CF, Kartagener syndrom (primary ciliary dyskinesia)

Clinical features:  Severe, persistent cough, dyspnea, foul smelling sputum

Complications: include hypoxemia with cor pulmonale and secondary amyloidosis

Clinical: Progressive dyspnea and cough: Fibrosis on lung CT (subpleaural to entire lung involvement): Treatment is lung transplantation: Crackles heard on inspiration

Morphological: Cobble stone pleural spaces, fibroblastic foci, honeycomb fibrosis

TGFB-1 causes fibroblastic foci

• o   Progressive dyspnea and cough
• o   Fibrosis on lung CT (subpleaural to entire lung involvement)
• o   Treatment is lung transplantation
• o   Crackles heard on inspiration

·       Dermatomyositis

·       Sjogren syndrome and other collagen vascular diseases

·       HIV – defining criterion for AIDS in children

·       Severe combined immunodeficiency

·       Pneumocystis; EBV; chronic hepatitis

·       Dysproteinemias: polyclonal gammopathy

Exposure: Coal

Pathogenesis is macrophages produce fibrogenic cytokines

Morphology + Clinical: from least harmful to worst:

anthracosis -> asymptomatic except w/ central acinal emphysema

simple CWP -> usually asymptomatic

complex CWP -> respiratory compromise, progressive

No TB or CA risk

Coexistence of lung disease of RA and pneumoconiosis (CWP, asbestosis or silicosis)

Exposure: Silica and Free radicals

Morphology: 1) Collagenous nodule i. birefrigent (sparkle) material II. calcification of lymph nodes; or 2) Progressive massive fibrosis

Clinical: Upper lobes (asymptomatic), respiratory compromise

TB RISK (only one), CA risk

Caplan syndrome (RA and pneumoconiosis)

Morphology: 1. Pleural plaque (most common) – incidental, not looking for it 2. Asbestosis (honeycomb/fibrosis) – pleural effusions, recurrent 3. Bronchogenic carcinoma (most common CA) 4. Mesothelioma – Peritoneal mesothelioma 5. Asbestos bodies (ferruginous bodies) stained with Prussian blue

Clinical:  Starts in lower lobes with alveolar duct fibrosis; linear densities on radiograph; May remain static or progress to cor pulmonale or death; Risk of developing bronchogenic carcinoma or mesothelioma (pleural or peritoneal)

No TB risk; CA risk

Morphology: Granuloma

No TB risk; CA risk increase