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15 Immunodeficiencies

A. Acquired causes of immunodeficiencies

1. Environmental (UV irradiation)

2. Drug induced (immunosuppressants)

3. non-HIV Viral (measles virus)

Dr. Andrea Hubbard

School of Pharmacy

andrea.hubbard@uconn.edu

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Structure and Function of the Skin

Layers:

•Epidermis (most superficial, continually renewing; keratinocytes, LC,

melanocytes, Merkel cell)

•Dermis (fibroblasts, DC, mast cells, collagen, elastin, microvasculature)

•Subcutaneous (fat)

Keratinocytes do not

express class II, but do make

numerous cytokines as

do mast cells in dermis

Immunodeficiencies: Environmental: UV irradiation

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Langerhans Cells

�epidermis and dermis

�Primary APC; highly class II positive

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Effects of different spectra of UV irradiation

•UVA minimal biologic activity (melanin)

•UVB (cell death, DNA damage)

•UVB also causes sunburn, suntan and

vitamin D formation

•UVC caused skin reddening; germicidal

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Benefits

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As we age, cell turnover in the epidermis

slows and the epidermis becomes thinner.

Also, the dermal-epidermal border

becomes less undulating. Notice the

difference in the thickness of the

epidermis between the aged skin slide

and the youthful skin slide.

1. Aging Skin

Harmful Effects

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2. Ocular Damage

3. Skin Cancer

•Basal cell, squamous cell

carcinoma

•Melanoma

Basal cell carcinoma

Melanoma 8

4. Initiate or aggravate photosensitivity

especially in patients with SLE, MCTD, etc

5. Photosensitivity in patients on

pharmaceutical compounds

Brand Name Generic Name Therapeutic Class

Motrin ibuprofen NSAID, antiarthritic

Crystodigin digitoxin antiarrhythmic

Sinequan doxepin antidepressant

Cordarone amiodarone antiarrhythmic

Bactrim trimethoprim antibiotic

Diabinese chlorpropamide antidiabetic (oral)

Feldene piroxicam NSAID, antiarthritic

Vibramycin doxycycline antibiotic

Phenergan promethazine antihistamine

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Immunosuppression from high dose UV and low dose UV10

6. Immunosuppression by UV irradiation

�Dependent on wavelength, total UV dose

�Suppression can be local (suppression achieved if antigen is applied

to UV irradiated skin) or systemic (UV applied to one site and hapten

to distant non irradiated site)

�Not dependent upon loss of epidermal LC, or sunburn or skin

pigment

�Low dose UVB irradiation induces inhibition of local

sensitization phase of CHS to a hapten applied to previously

irradiated skin; no effect on non irradiated skin

�High dose UVB induces inhibition of the systemic sensitization

phase of CHS to hapten and DTH to alloantigen when antigen is

injected into distant non irradiated site (probably due to

systemic IL-10, TNFα, & T regs)

�Both kinds of immunosuppression are genetically restricted (at

least in mice; ? humans) 11

�Measured by CHS which is special form of DTH induced by

epicutaneous application of low MW haptens (DNFB). In

experiments designed to investigate local immune suppression, mice

were exposed to UV and a hapten chemical such as

dinitrofluorobenzene (DNFB) was applied to the site of irradiation.

After an incubation period of several days, animals were challenged

by painting the chemical on the ear, and the immune response was

assessed by measuring ear thickness, which is an expression of

CHS. 12

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Initial step is absorption by chromophores (DNA, UCA, melanin) at or

near body surface (photoreceptors)

•DNA damage of keratinocytes (IL-10)

•Trans to cis isomerisation of urocanic acid (UCA)

•Membrane changes (oxidative stress & membrane lipid peroxidation)

•Alteration of LC number, morphology and APC

•Induce T regs

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Erythemal doses of UV radiation induce systemic immune

suppression by the release of cytokines, soluble

mediators, and altered function of antigen presenting cells

to induce antigen-specific regulatory T cells. 16

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Suppression immune response and skin cancer in humans

�UVR suppresses CHS are termed susceptible (UVS) (35%)

�No suppression of CHS are termed resistance (UVR) (65%)

�92% of non melanoma skin cancer (basal cell, squamous cell)

and 100% of malignant melanoma ins UVS group

Ullrich SE. Mechanisms Underlying UV induced Immune

Responses. Mutation Res 571:185-205 (2005) 18

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More donors

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Immunodeficiencies: 2. Drug induced

Organ Transplantation and IS Drugs

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Autologous

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1. Necessary to match blood group proteins

In selecting donor/recipient matches:

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2. Necessary to match HLA proteins (esp A, B and D)

HLA-D HLA-A, B or C

MHC class I found

on nearly every

nucleated cell;

presents Ag to

cytotoxic T cells

MHC class II found

B cells, macrophages,

APC; presents Ag to

T helper cells

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Hyperacute

Acute

Chronic

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2. Acute

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1. Human skin allograft on day 5

(fully vascularized)

2. On day 12 (totally destroyed)

3. Second graft from same donor on day 7

(no vascularization) 28

Acquired Immune Tolerance in the

absence of immunosuppressive drugs.

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Other sides effects from transplantation:

•Infections•Cancer

•ADE

Acu

te rejection

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Treatment of Rejection

Induction:

•corticosteroids

•anti-thymocyte globulins

•anti-CD3

•anti-IL-2R

Maintenance:

•azathioprine

•mycophenolate

•cyclosporin

•tacrolimus

•sirolimus

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Mechanism of Action

•Found to be selective for T lymphocytes

•Inhibition of proliferation w/o affecting bone marrow cells

•Prevented T lymphocyte proliferation & activation

•Approved by FDA in 1983 for kidney transplants

•Major adverse effects: fever diarrhea, vomiting,

tingling, nephrotoxicity/hepatotoxicity, increased

susceptibility to infections, inability to prevent chronic

rejection

•Marketed by Novartis as Sandimmune; Neoral

(microemulsion)

Cyclosporin

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Approved kidney, liver, heart, lung, heart-lung, bone marrow

transplants as well as autoimmune diseases (e.g. psoriasis,

atopic dermatitis, RA)

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Tacrolimus (FK506)

•In 1984, compound from soil sample taken at foot of

Mt. Tsukuba (Tokyo)

•Streptomyces tsukubaensis

•Similar to CyA in MOA; more potent immunosuppressive drug

•In 1986, began clinical trials (Fujisawa Pharm and Univ

of Pittsburgh Med. School)

•In 1990, found efficacy in preventing rejection of liver transplants

•In 1994, marketed as Prograf and approved by FDA

•Adverse effects: hyperglycemia, nephrotoxicity, chest pain, etc

•MOA: Binds FKBP and inhibits calcineurin

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Tacrolimus approved for liver & kidney transplants; tablets of 0.5,1

or 5 mg

Tacrolimus also approved as an ointment in atopic eczema

(Elidel (pimecrolimus) Cream and Protopic (tacrolimus) Ointment)

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Sirolimus (Rapamycin) : MOA

•Structurally similar to FK506

and binds to FKBP

•Does not bind calcineurin or

inhibit IL-2

•Blocks progression through cell

cycle

•Synergistic with CyA

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•Major adverse effects: hyperlipidemia, leukopenia,

thrombocytopenia

•In 1999, approved as immunosuppressive drug by FDA

•Used in renal transplants; off label for psoriasis

• Everolimus approved in cancer chemotherapy (RCC)

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Rapamycin blocks T and B cells from responding

to cytokines and thus prevents progression from

the G1 phase (synthesis of RNA and protein) to

the S phase (synthesis of DNA). Cell proliferation

is therefore inhibited.

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FK506 FKBP

CyA

Calcineurin

(A)

Cyclophilin

FKBP

Rap

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Immunodeficiencies:

3. non-HIV viral: measles virus (Rubeola)

• Enveloped, negative-sense, non segmented RNA virus

• Naturally infects only humans; 1 million deaths worldwide

mostly children under age 5

• Highly infectious by respiratory route

• Attenuated virus vaccine (lower titers than natural infection)

• Natural infection provides life long immunity, but also

suppresses immune system increasing susceptibility to

secondary infections

• Immune suppression is coincident with immune system

activation and MV specific responses; can continue

for several wks

• Apparent as loss of DTH skin test response,

impairment of CMI and HMI, reactivity of TB and

remission of autoimmune disease (JRA)

• Abs in natural infection appears with rash 44

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• Secondary infections: pneumonia, chronic pulmonary disease,

otitis media, larynogotracheobronchitis ARDS, hepatitis and

diarrhea. Accounts for most of morbidity/mortality in acute

measles.

• Recovery depends on CMI; however MV causes defect in

Thelper populations.

• Mechanism of MV induced immunosuppression

o No affect on cytokines (IFNγ, IL-2, IL-6, IL-10)

o Defect in component of IL-2 receptor

o Elevation in IL-4/decrease in IL-12 which could change

Th1:Th2 polarization

o MV interaction with its receptor CD46 suppression of IL-12

o Infection of macrophages, not lymphocytes causes apoptosis

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