glucocorticoid effects on the immune system

EFFECTS ON THE IMMUNE SYSTEM

GLUCOCORTICOID

Jaichat Mekaroonkamol, MD.

OUTLINES

• Introduction• Synthesis and action• Effects on immune systems• Impact on vaccination• Impact of dose• Infection risk

CORTISONE AS A SYMPTOMATIC TREATMENT OF RHEUMATOID

ARTHRITIS

STEROID IN CLINICAL USED

• Allergic and respiratory disordersAnaphylactic shock , atopic dermatitis , asthma , chronic rhinitis , chronic bronchitis , emphysema

• Autoimmune disordersRheumatoid arthritis , systemic lupus erythematosus , systemic vasculitis , polymyalgia rheumatica , temporal arteritis , autoimmune hemolysis , myasthenia gravis , Graves’ ophthalmopathy

• Dermatologic disordersEczema , contact dermatitis , irritant dermatitis , stasis dermatitis , seborrheic dermatitis , exfoliative dermatitis , psoriasis , lichen striatus , lichen planus , lichen nitidus , vitiligo , pruritus ani

Williams Textbook of Endocrinology, 1998; 517-664

STEROID IN CLINICAL USED

• Gastrointestinal disordersUlcerative colitis , Crohn’s disease , chronic active hepatitis , subacute hepatic necrosis , alcoholic hepatitis , non-alcoholic cirrhosis

• Renal disordersNephrotic syndrome , lupus nephritis , rapid progressive glomerulonephritis

• MalignanciesLymphoma , leukemia , breast cancer

• Graft rejectionKidney , heart , lung , liver and other tissue transplantation

• OthersSarcoidosis, vitamin D intoxication , septic shock , cerebral edema , spinal cord injury , hypercalcemia , Bell’s palsy, conjucntivitis , keratitis , etc.

Williams Textbook of Endocrinology, 1998; 517-664

SYNTHESIS

SYNTHESIS

• Adrenal production of HC and aldosterone• Cholesterol progenolone intermediate

progesterone hydroxylate at 17-,21-, and 11-positions HC

• High dose GC >1 wk suppress HPA axis

IAN M. ADCOCK and KIAN FAN CHUNG. Middleton’s Allergy, 8th ed

Rhen T et al. N Engl J Med 2005;353:1711-23

Neuroendrocrine regulation of inflammation•Hyperactivity of HPA: Cushing’s syndrome, stress

• Immunosuppres sion

•Decrease HPA• Severe

inflammation

Oral and topical GCs pass rapidly through the cell membrane by passive diffusion into the

cytoplasm


Genomic effects

Nongenomic effects

Glucocorticoid receptor

GLUCOCORTICOID RECEPTOR

• Intracellular receptor• Member of the nuclear receptor family• Present in virtually all cells, including

those of the immune system• Highest affinity for dexamethasone



Bind GR Direct genomic effects


Enables GR to associate with transcriptional coactivators or

repressorsIndirect genomic

effects

HUMAN HR PROTEIN

• hGRα • Primary form of GR

• Vary expression between cell type

• Bind GCs• If reduced by up to 70%

not enough to prevent effective antiinflammatory response

• hGRβ• Lacks a ligand-binding

domain• Does not bind GCs• Increase expression in

GCs resistant and decrease ability of hGRα to bind to GRE


MECHANISM OF ACTION



Genomic effects

Nongenomic effects

Direct effects

Indirect effects

TRANSCRIPTION

GENOMIC MECHANISMDIRECT EFFECTS

• Binding of the receptor to GREs may result in either enhancement or suppression of transcription of susceptible downstream genes



Genomic effects

Indirect effects

Interactions between the cortisol glucocorticoid receptor complex and other transcription factors, such as

nuclear factor B (NFB)

Barnes. Br J pharmacol: Respiratory Pharmacology Issue Revised. 2010

GC activation antiinflammatory gene expression

GC suppression of activated inflammatory gene expression

Barnes. Br J pharmacol: Respiratory Pharmacology Issue Revised. 2010

Middleton’s Allergy, 8th ed

MECHANISM OF ACTION


NON-GENOMIC MECHANISM

Rhen T et al. N Engl J Med 2005;353:1711-23.

Inhibit prostaglandin production•Induction and activation of annexin I•Induction of MAPK phosphatase 1•Repression of transcription of cyclooxygenase 2

Buttgereit F et al. Arthritis Rheum 41:761–767, 1998.

• The dosage is increased up to approximately 200 to 300 mg of prednisone equivalent per day

• Negative feedback of ACTH production

• Inhibit effect on lymphocyte activation

Buttgereit F et al. Arthritis Rheum 41:761–767, 1998.

• Membrane-bound receptors• The antianaphylacticactions of

glucocorticoids may be explained by this mechanism.

Cassidy. Textbook of pediatric rheumatology. 5th edition

OUTLINES


EFFECTS ON IMMUNE SYSTEMS


• Effects on leukocyte trafficking

• Effects on innate immunity

• Effects on acquired immunity

EFFECTS ON LEUKOCYTE TRAFFICKING

• Glucocorticoids have profound effects on the cellular functions of leukocytes and endothelial cells• Reduced ability of leukocytes to adhere to vascular

endothelium and exit from the circulation. • Entry to sites of infection and tissue injury is impaired

suppression of the inflammatory response

Fauci AS et al. Ann Intern Med 1976; 84:304.Fauci AS et al. Cell Immunol 1980; 49:43.

Boumpas DT et al. Ann Intern Med 1993; 119:1198.


Fauci AS et al. Ann Intern Med 1976; 84:304.Fauci AS et al. Cell Immunol 1980; 49:43.

Boumpas DT et al. Ann Intern Med 1993; 119:1198.

• Reduction in endothelial adhesion • Direct effects

• on expression of adhesion molecules on both leukocytes and endothelial cells

• Indirect effects• the inhibitory effects of glucocorticoids on transcription

of cytokines(IL-1/TNF) that upregulate endothelial adhesion molecule expression.


1. Fauci AS et al. Ann Intern Med 1976; 84:3042. Cox G. J Immunol 1995; 154:4719

3. Andersen V et al. Cell Tissue Kinet 1969; 2:1394. Nagase H et al. J Allergy Clin Immunol 2000; 106:1132

5. Meagher LC et al. J Immunol 1996; 156:4422

• Increased numbers of circulating neutrophils1,2 • Neutrophil migration through the vasculature to sites of

inflammation is severely impaired• Enhanced release of cells from the bone marrow• Inhibition of neutrophil apoptosis

• Circulating levels of eosinophils are markedly and rapidly reduced3

• Sequestration of eosinophils in extravascular tissues, possibly due to the preferential upregulation of the CXCR44

• Induce apoptosis of eosinophils5

• notably dexamethasone


• Tissue accumulation of monocytes and macrophages is reduced• Decreased migration from the vasculature• Reduced elaboration of macrophage migration inhibition

factor

• The numbers of circulating T lymphocytes are rapidly reduced and B lymphocyte numbers are reduced to a lesser extent

Gerlag DM et al. Arthritis Rheum 2004; 50:3783Balow JE et al. J Exp Med 1973; 137:103

EFFECTS ON INNATE IMMUNITY

EFFECTS ON INNATE IMMUNITYPHAGOCYTES

• Neutrophils • In vitro studies: inhibit neutrophil apoptosis1,2

• Neutrophil phagocytic responses or bactericidal activities do not appear to be significantly impaired, although, at high doses, phagocytic function may be inhibited3,4

• The main impact: impairment of migration to sites of inflammation or infection

1. Fauci AS et al. Ann Intern Med 1976; 84:3042. Meagher LC et al. J Immunol 1996; 156:44223. Jones CJ et al. Ann Rheum Dis 1983; 42:56

4. Herzer P et al. Immunobiology 1980; 157:78


• Eosinophils• Promote eosinophil apoptosis

• attenuating synthesis of interleukin-5 (IL-5), a cytokine that promotes eosinophil survival. 1,2

• Variable inhibitory effects upon the degranulation of eosinophils that are dependent upon the activating ligand and the glucocorticoid used in the assay3

• Methylprednisolone inhibited degranulation of normodense eosinophils up to 20%, hypodense eosinophils up to 30%

1. Meagher LC et al. J Immunol 1996; 156:44222. Wallen N et al. J Immunol 1991; 147:3490

3. Kita H et al. J Allergy Clin Immunol 1991; 87:70


• Monocytes and macrophages • Diminish the production of

monocyte/macrophage-derived eicosanoids and inflammatory cytokines (IL-1, TNF, IL-6)1

• Inhibit macrophage phagocytic and microbicidal function2

• Clearance of opsonized bacteria by the reticuloendothelial system is reduced 3

• Reduce Intracellular killing of Nocardia, Listeria, and Salmonella4

1. Fauci AS et al. Ann Intern Med 1976; 84:3042. Rinehart JJ et al. N Engl J Med 1975; 292:236

3. Atkinson JP et al. Blood 1974; 44:6294. IAN M. ADCOCK and KIAN FAN CHUNG. Middleton’s Allergy, 8th ed

EFFECTS ON INNATE IMMUNITYMAST CELL & BASOPHILS

• In vitro: inhibit both production of cytokines and degranulation by mast cells. • The noted inhibition of inflammatory cytokine

production• suppression of gene transcription

• The inhibition of mast cell degranulation• upregulation of inhibitory regulators of signaling, such

as SLAP1 (src-like adapter protein-1)

• Prednisolone treatment in vivo reduces airway basophilia

Andrade MV et al. J Immunol 2004; 172:7254Nakamura R et al. Immunol Lett 2005; 98:272

Park SK et al. Mol Immunol 2009; 46:492IAN M. ADCOCK and KIAN FAN CHUNG. Middleton’s Allergy, 8th ed

EFFECTS ON INNATE IMMUNITYPROINFLAMMATORY MEDIATORS

• Degrade bradykinin, which is a vasodilatory peptide central to the generation of some forms of angioedema

• Upregulating the synthesis of angiotensin-converting enzyme and neutral-endopeptidase enzymes

Borson DB et al. Am J Physiol 1991; 260:L83


• Suppressing production of inflammatory eicosanoids in phagocytic cells• inducing the synthesis of lipocortin-1 (annexin

I), macrocortin, and/or lipomodulin, all of which inhibit phospholipase A2 (PLA2)-mediated liberation of arachidonic acid from membrane phospholipids

Flower RJ et al. Nature 1979; 278:456Hirata F et al. Proc Natl Acad Sci U S A 1980; 77

Kim SW et al. J Biol Chem 2001; 276:15712


• Suppressing the synthesis of cyclooxygenase-2 (COX-2)1

• suppression of nuclear factor kappa B (NF-kB) transcription.

• Glucocorticoids do not appear to affect the synthesis of constitutive cyclooxygenase-12.

1 Chen CC et al. J Immunol 2000; 165:27192 Chatham WW, UpToDate 2014



• Effects on leukocyte trafficking

• Effects on innate immunity

• Effects on acquired immunity

EFFECTS ON ACQUIRED IMMUNITY

EFFECTS ON ACQUIRED IMMUNITYANTIGEN PRESENTING CELLS

• Dendritic cells and macrophages• Suppress expression of MHC II molecules on

macrophages1,2

• Decrease the numbers of both circulating and organ-resident dendritic cells3

• Induced apoptosis of resident dendritic and/or CD34+ precursor-derived CD14+ dendritic cells 4

1 van de Garde MD et al. J Immunol 2014; 192:11962 Schwiebert LM et al. Cell Immunol 1995; 165:12

3 Shodell M et al. Lupus 2003; 12:2224 Woltman AM et al. J Immunol 2002; 168:6181

EFFECTS ON ACQUIRED IMMUNITYT CELLS

• Enhanced circulatory emigration1 ( upregulate CXCR4)

• Induction of apoptosis depend upon the stage of T cell differentiation and T cell subtype

1 Fauci AS et al. Ann Intern Med 1976; 84:3042 Ashwell JD et al. Annu Rev Immunol 2000; 18:309

3 Cohen JJ et al. J Immunol 1984; 132:384 Lanza L et al. Clin Exp Immunol 1996; 103:482


• T cell lineage commitment• inhibit the acute generation of both Th1- and

Th2-derived cytokines by activated T cells

Franchimont D et al. Regul Pept 1998; 73:59

Th1 Th2IL-2IL-3

TNF-IFN-

IL-4IL-5IL-6

IL-13


• T cell lineage commitment• attenuate peripheral blood mononuclear cell

production of IL-12• Undifferentiated T cells to the Th1 and Th17

lineage• minimal effect on production of IL-10

Visser J et al. Blood 1998; 91:4255Weaver CT et al. Immunity 2006; 24:677

Weaver CT et al. Immunity 2006; 24:677


• Regulatory T cell• Enhance the induction of IL-10 expression• Enhance transcription factor Foxp3+ (alone or vitamin

D3)• Dramatic potentiation of CTLA4 expression

• CTLA4 contain ITIM and may be centrally involved in T cell tolerance

• Induction by steroids of CTLA-4 and Treg cell could therefore potentiate tolerogenic response of T cells


EFFECTS ON ACQUIRED IMMUNITYB CELLS AND ANTIBODY PRODUCTION

• Reduced numbers of circulating B lymphocytes• but to a much lesser extent than those of T cells1

• Synthesis of antibodies by B cells remains essentially unchanged following short-term administration2

• but mild to modest decreases in serum immunoglobulin G (IgG) levels have been observed following short (eg, two to four week) courses of glucocorticoids

• Enhancing effects of glucocorticoids on IL-4 induced B cell isotype switching to IgE3

• Inhibit seasonal increase in IgE level in AR Pt4

1 Slade JD et al. J Lab Clin Med 1983; 101:479 2 Settipane GA et al. J Allergy Clin Immunol 1978; 62:162

3Jabara HH et al. J Immunol 1991; 147:15574 IAN M. ADCOCK and KIAN FAN CHUNG. Middleton’s Allergy, 8th ed

Bohle b et al. Clinical and Experimental Immunology,1995;101:474-479

Fedor ME et al. Ann Allergy Asthma Immunol 2006; 97:113

• A 54-year-old female schoolteacher• nasal congestion, nasal polyposis requiring 3

polypectomies,chronic sinusitis, and a 40-year history of asthma.

• Medications at the time of evaluation• Methylprednisolone 4 to 8 mg/d for 36

years• Montelukast 10 mg/d• Albuterol as needed for wheezing• Alendronate, 10 mg/d• Calcium 200 mg/d, vitamin D 0.125 mg/d.



These abnormalities resolved within 2 years after tapering of corticosteroid therapy

OUTLINES


IMPACT ON VACCINATION

• 14 adult steroid-dependent asthmatics• receiving daily or alternate day prednisone, 10

to 35 mg• 14 age-matched nonsteroid dependent asthmatic

patients• polysaccharide antibody levels against serotypes

3, 7F, 9N, and 14

All patients either had or developed levels > or = 300 ng Ab N/mL against one or more

pneumococcal serotypes after 4 week immunization

Lahood N et al. Ann Allergy. 1993 Apr;70(4):289-94

• 27 steroid-responsive and six steroid-resistant patients with nephrotic syndrome

• 12 age-matched control subjects

• Significantly depressed in steroid-resistant patients

• Steroid-responsive nephrotic children who were not receiving corticosteroid therapy at the time of vaccination had significantly higher antibody concentrations compared with control subjects

• Fewer steroid-responsive patients receiving corticosteroids achieved antibody concentrations greater than or equal to 200 ngN/ml against type 19F

Spika JS et al. Pediatrics. 1982 Feb;69(2):219-23

• 32 healthy volunteers • 62 patients with systemic lupus erythematosus

(SLE), rheumatoid arthritis, degenerative joint disease, and other rheumatic diseases.

• examined at the time of immunization and one week, three weeks, and four months later

• Administration of these vaccines was safe in these patients with stable disease and induced antibody responses in most individuals.

• Antibody responses to A/New Jersey/76 were significantly lower in young patients taking glucocorticoids compared to those not taking glucocorticoids.

Herron A et al. JAMA. 1979 Jul 6;242(1):53-6

influenza HA1 (A/Beijing), HA2 (A/Taiwan), and HB (B/Panama)

• A without corticosteroid therapy• B oral corticosteroid therapy : median corticosteroid dose 10.0

mg/day (2.5–25 mg/day), equivalent to prednisolone)• C inhaled corticosteroid therapy: median inhaled corticosteroid

dose: 800 μg/day (400–1600 μg/day), equivalent to budesonide)

Sumito Inoue et al. EXCLI Journal 2013;12:760-765

Sumito Inoue et al. EXCLI Journal 2013;12:760-765

control OCS ICS


• In patients who do show evidence of impaired vaccine response, removal of chronic low-dose glucocorticoid treatment may result in improved antibody production



• Immunosuppression due to chronic glucocorticoid use is a contraindication to the administration of live virus vaccines, such as measles, mumps, rubella (MMR), varicella, and vaccinia (small pox).

CDC 2011Chatham WW et al. UpToDate 2014

LIVE VIRUS VACCINES

OUTLINES


IMPACT OF DOSE

• Some immunologic effects of glucocorticoids are dose dependent• variable affinity of target genomic sites for the

complex of glucocorticoid and glucocorticoid receptor

• Administration of high-dose pulse glucocorticoids • may result in nonspecific general disruption of gene

transcription• may also have more rapid effects on leukocyte

aggregation, possibly as a consequence of effects on the expression of leukocyte adhesion molecules and disruption of calcium flux across membranes

Hammerschmidt DE et al. J Clin Invest 1979; 63:798Youssef P et al. J Rheumatol 1995; 22:2065

IMPACT OF DOSELOW TO MODERATE DOSES

• T lymphocytes may be slightly reduced in the circulation• CD4-positive cells more than CD8-positive T cells1

• Delayed-type hypersensitivity (DTH) responses may be impaired2

• the failure of inflammatory cells to be recruited to the site of the reaction cutaneous anergy

Less than 2 mg/kg per day of prednisone in children or less than 40 mg per day in adults

1 Haynes BF et al. J Clin Invest 1978; 61:703 2 Chatham WW et al. UpToDate 2014

Fan PT et al. J Lab Clin Med 1978; 91:625

• We treated two groups of six patients with classic RA with either one or three daily 1 gm intravenous doses of MPS

• Measured the immune response and clinical activity over 16 weeks.

• Lymphopenia developed within two hours , peaked at six hours and resolved by 24 hours with both regimens.

• Patients were followed for 16 weeks• PPD was unaffected, serum immunoglobulin levels

were unchanged, and primary antibody responses to antigens were normal

• Higher and repeated doses of MPS caused neither greater lymphocytopenia nor more prolonged suppression of recirculating lymphocytes than the conventional oral doses.

OUTLINES

• Introduction• Synthesis• Effects on immune systems• Impact on vaccination• Impact of dose• Infection risk

INFECTION RISKSYSTEMIC GLUCOCORTICOID THERAPY

• Dose-dependent increase: inhibitory effects on phagocytic cell function.

• With long-term, low-dose use, effects on phagocytic cell function are minimal, but there may be some inhibition of adaptive immune responses with increasing duration of therapy.

Chatham WW et al. UpToDate 2014

INFECTION RISKINHALED AND TOPICAL CORTICOSTEROID

• Inhaled and topical corticosteroids are usually not implicated in increased risk of systemic infections


INFECTION RISK

• Various patient-specific factors influence infection risk• underlying disorder• presence of concomitant immunosuppressive therapies• patient is hospitalized.

• patients taking glucocorticoids may not manifest signs and symptoms of infection as clearly, due to the inhibition of cytokine release and associated reduction in inflammatory and febrile responses. This can impair early recognition of infection.


INFECTION RISK

• A meta-analysis of controlled trials in which glucocorticoids or placebo were given• infection occurred significantly more often with

steroid therapy (12.7 versus 8.0 percent with placebo, relative risk 1.6)

• average dose of prednisone of more than 10 mg/day or a cumulative dose of greater than 700 mg.

Stuck AE et al. Rev Infect Dis 1989; 11:954

INFECTION RISK

• 223 patients with lupus who were not receiving other immunosuppressive agents

• The risk of infection rose from 1.5-fold at an average prednisone dose below 10 mg/day to over eightfold in patients receiving doses above 40 mg/day.

Ginzler E et al. Arthritis Rheum 1978; 21:37

INFECTION RISKTYPES OF INFECTIONS

• Herpes zoster• more commonly among patients taking low-

dose • A retrospective cohort analysis of over 200

patients with RA found that eight patients treated with glucocorticoids developed zoster compared with only one control1

• However, people receiving glucocorticoid may have had closer surveillance, potentially leading to more cases of herpes zoster detected.

1 Saag KG et al. Am J Med 1994; 96:115


• Tuberculosis• concern in patients receiving moderate to high

doses of glucocorticoids for prolonged periods of time

• Reactivation of latent Strongyloides• hyperinfection syndrome that can be fatal

• Other helminthic or protozoan infections• unusual, except in areas of the world where they are

endemic (eg, P. falciparum).



• Opportunistic infections • only in patients with very significant

immunosuppression• prolonged glucocorticoids+immunosuppressant drugs• underlying immunosuppressive conditions

• Pneumocystis carinii (P. jirovecii) pneumonitis is associated with the use of glucocorticoids, both with chronic use of moderate doses and short-term use of high doses


INFECTION RISKMEASURES TO REDUCE RISK

• Use of short-acting preparations (such as prednisone) given every other day

• In one retrospective report of 70 patients with various inflammatory conditions treated with alternate day prednisone at mean doses of 45 to 60 mg daily, none developed serious infections

Fauci AS et al. Ann Intern Med 1976; 84:304.

TAKE HOME MESSAGE (1)

• Diffuse across the cell membrane and bind to the intracellular GR to form a complex that translocates into the nucleus.

• Genomic and Non-Genomic mechanism • Neutrophilic leukocytosis, accompanied by

dramatic reductions in circulating eosinophils, monocytes, and lymphocytes

• Effects on the innate immune system include dose-dependent impaired phagocyte function and attenuated production of proinflammatory mediators.

• Glucocorticoids impair a variety of T cell functions and induce T cell apoptosis.

• B cells are less affected and antibody production is largely preserved, although a mild decrement in immunoglobulin G (IgG) and immunoglobulin A (IgA) levels may develop in some patients with chronic use.

• Immunoglobulin E (IgE) levels may increase.


• Vaccine responses are preserved in most patients on chronic low to moderate doses of glucocorticoids, although the titers may be reduced in some individuals.

• Low to moderate dose may be impairedIn T cell function but immunoglobulin levels are usually normal or only slightly low.

• High-dose, short-term pulse therapy results in dramatic changes in levels of circulating leukocytes, but relatively intact immunologic functions immediately after administration


• Systemic glucocorticoid therapy is associated with a dose-dependent increase in the risk of infection• common viral, bacterial, and fungal pathogens• Opportunistic infections are less common, and

are mainly a concern in patients taking other immunosuppressive agents or with diseases causing immunocompromise.


glucocorticoid effects on the immune system

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