Journal of Medicinal Plants Research Vol. 6(7), pp. 1100-1105, 23 February, 2012 Available online at http://www.academicjournals.org/JMPR DOI: 10.5897/JMPR11.

1401 ISSN 1996-0875 2012 Academic Journals

Review

Autoimmune diseases and immunomodulant plant

M. M. Akram1, M. Saim Jamil1, Zahid Mehmood2, Khan Usmanghani1, Iqbal Azhar4, Muhammad Akram5, H. M. Asif3 and Umar Iqbal1
2

Shifa ul Mulk Memorial Hospital, Hamdard University, Karachi, Pakistan. Department of Chemistry and Biochemistry, University of Agriculture, Faisalabad, Pakistan. 3 Department of Pharmacy, The Islamia University of Bahawalpur, Pakistan. 4 Department of Pharmacognosy, University of Karachi, Pakistan. 5 Department of Pharmacy, University of Sargodha, Pakistan.
Accepted 4 November, 2011

The immune system in general responds appropriately to the presence of foreign antigens. Body immune system protects the body against invading organisms. In an autoimmune disease, immune system attacks healthy cells in body by mistake. Autoimmune diseases can affect many parts of the body. Various plants are used to strengthen the immunity due to their immunomodulatory activities. In this article, autoimmune diseases, description of autoimmune diseases, and plants used as immunomodulant agent has given. Key words: Autoimmune diseases, immunomodulatory activity, medicinal plants, research study.

INTRODUCTION Autoimmune disorders are disorders in immune regulation resulting in antibody or cell mediated immunity against the hosts own tissues (Table 1). Autoimmune disorders may or may not result in injury to the host. Autoimmune disorders are disorders in which persons are normally unresponsive to self antigens due to tolerance; however, B-cell clones do exist in persons with idiotypes reacting with self antigens. Autoimmune diseases include systemic lupus erythematosis (RuizIrastorza, 2010; Hahn et al., 2008), primary central nervous system (CNS) vasculitis, rasmussen's encephalitis, autoimmune peri-pheral neuropathy, autoimmune cerebellar degeneration, autoimmune thrombocytopenia (Segal et al., 2006), gait ataxia with late age onset polyneuropathy, stiff person syndrome, chronic inflammatory demyelinating poly-neuropathy, myasthenia gravis and multiple sclerosis. Hashimotos thyroiditis is a chronic autoimmune disease characterized by immune destruction of the thyroid gland and hypothyroidism. Graves disease is autoimmune disease characterized by production of immunoglobulin G (IgG) auto-antibodies to the thyroid stimulating hormone (TSH) receptor. Addisons disease occurs due to destruction of adrenal cortex leading to a deficiency of glucocorticoids, mineralocorticoids and androgens. Rheumatoid arthritis (RA) is a systemic chronic and inflammatory disease characterized by progressive arthritis, production of rheumatoid factor and extra-articular manifestation. It is thought to be caused by an autoimmune reaction triggered by an infectious agent in a genetically susceptible individual (Meroni et al., 2010; Fritzler, 2011). Myasthenia gravis is an autoimmune disease characterized by autoantibodies against the neuromuscular junction, resulting in muscular weakness. Vitiligo is characterized by irregular, completely depigmented patches. It may affect any race. Insulin dependent diabetes mellitus is thought to be caused by an autoimmune reaction triggered by an infection (Coxsakie B virus) in a genetically susceptible individual. It represents 10% of cases of diabetes. It affects children and adolescents usually younger than 20. Asparagus racemosus have also shown immunopotentiating effects in cyclophasphamide treated mouse with ascetic sarcoma (Diwanay et al., 2004). Kalita and Dutta (1999) reported that maternal antibody was persistently found in sera samples tested against ND virus during the first week of age in broilers. This was attributed to transfer of

*Corresponding author. E-mail: makram_0451@yahoo.com. Tel: 92 021 6440083. Fax: 92 021 6440079.

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Table 1. Autoimmune classification.

Disease Juvenile insulin-dependent diabetes Pernicious anemia Addison's disease Idiopathic hypoparathyroidism Autoimmune hemolytic anemia Idiopathic thrombocytopenic purpura Idiopathic neutropenia Vitiligo Chronic active hepatitis Goodpasture's syndrome Rheumatoid arthritis Sjogren's syndrome Systemic lupus erythematosus Myasthenia gravis Graves disease Thyroiditis Insulin-resistant diabetes Asthma

Antibody against Pancreatic islet cells Gastric parietal cells Adrenal cells Parathyroid cells Erythrocytes Platelets Neutrophils Melanocytes Nuclei of hepatocytes Basement membranes Gamma globulin, virus-related antigens Nuclei and centromeres Nuclei, DNA, RNA, erythrocytes, etc. Acetylcholine receptors Thyroid-stimulating hormone receptor Thyroid Insulin receptor Beta-2 adrenergic receptors

natural passive immunity in young chicks as demonstrated by Hellar (1975).

(multiple myeloma). Central nervous system

EXPLANATORY DISORDERS

THEORIES

FOR

AUTOIMMUNE

1. Microbial antigens cross reacting with host tissues induce an immune response against self, 2. Host antigen previously sequestered from fetal tolerance-inducing mechanism are released and become immunogenic, 3. Alteration of host molecules, exposing new antigenic determinants unavailable at the time of induction of fetal tolerance, 4. Attachment of foreign hapten to self molecule, forming a hapten carrier complex, 5. Depletion of suppressor cells. SYSTEMIC AUTOIMMUNE DISORDERS 1. 2. 3. 4. Systemic lupus erythematosis, Rheumatoid arthritis, Sjogrens syndrome, Polyarteritis nodosa.

1. Allergic encephalitis, 2. Multiple sclerosis, 3. Myasthenia gravis. Endocrine 1. Chronic thyroiditis, 2. Graves disease, 3. Diabetes mellitus. Gastrointestinal tract 1. Pernicious anemia, 2. Ulcerative colitis, 3. Crohn disease, 4. Chronic active hepatitis. DISEASES INVOLVING PRIMARILY ONE TYPE OF CELL OR ORGAN Myasthenia gravis

ORGAN SPECIFIC AUTOIMMUNE DISORDERS Blood 1. Autoantibodies reacting with blood cells, 2. Malignant transformation of a single plasma cell clone

This acquired condition is characterized by weakness and fatigability of proximal limb, ocular and bulbar muscles. The heart is not involved. The cause is unknown. IgG antibodies to acetylcholine and acetylcholine receptor proteins are found. Immune complexes (IgG and

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complement) are deposited at the postsynaptic membranes causing interference with and latter destruction of the acetylcholine receptor. The prevalence is about 4 in 100,000. It is twice as common in women as in men, with a peak incidence around the age of 30 years. Occurrence It occurs in one of 20, 000 persons.

cells (Dormant B- lymphocytes in lymphoid tissue). Each plasma cell makes 2000 molecules of antibodies (gamma-globlins). Production of antibodies Antigens stimulate proliferation of lymphoid resulting in the production of antibodies. Nature of antibodies cells,

Causes It is caused by antibodies directed against the achreceptors of the muscle fibers of sarcolemma. The antibodies are bind to receptors and hinder the attachment of ach to the receptors. As the disease progresses, more neuromascular junctions become affected. Clinical features This disease is more common in females between the ages of 20 to 50 years. The muscles of the face and neck are mostly involved. Initial symptoms include a weakness of the eye muscles and difficulty in swallowing. Later, the individual has difficulty in chewing and talking. Eventually, muscles of the limbs may become involved. Death may result from the paralysis of respiratorymuscles. Treatment Anticholinesterase drugs such as neostigmine and pyriodostigmine derivates of physostigmine are advised to be used. Antibodies These are substance made in response to antigenic stimuli. They are found in plasma and are developed from small lymphocytes. Sites of antibodies production central lymphoid system These are lymphoid tissue of the thymus gastroinal tract (peyers patches, tonsils, appendix). Peripheral lymphoid organs Lymph nodes and spleen have lymphocytes and plasma cells. Formation of antibodies by plasma cell All Ig are made and secreted actively by plasma Minor groups: They are 1 gE, 1 gD and 1 gD. Gravess disease Graves disease accounts for about 85% of all hyperthyroidism. It occurs most frequently in young women, although it can occur in either sex at any age. Susceptibility is certainly multigenic but has been associated with the human leukocyte antigen (HLA)-DR3 haplotype in the major histocompatibility complex (MHC) locus. It is generally characterized by hyperthyroidism and diffuse thyroid enlarement and the presence of circulating antibodies directed against the TSH receptor on the membrane of the thyroid gland. Three types of antibodies may be found. These are gamma-globulins or 1 g found free in serum and on the surface of lymphocytes. In plasma cells, they are found inside the cells. Major functions of antibodies: They neutralize the toxins viruses, and also opsonize bacteria, making them easier to phagocytize. Concentration (normally): It is normally 1.6 gm/100 ml of blood. Molecular weight: It is between 150,000 to 900,000 (unit) structures of a typical 1g molecule four polypeptide chains. Two heavy chains: Molecular weight, 20,000 (unit); Each chain has 450 amino acids. Major groups: They are 1Gg, 1Gm and 1gA.

Diabetes mellitus This form of diabetes is immune-mediated in over 90% of cases and idiopathic in less than 10%. The rate of pancreatic B cell destruction is quite variable, being rapid in some individuals and slow in others. Type I diabetes is usually associated with ketosis in its untreated state. It occurs at any age but most commonly arises in children and young adults with a peak incidence before school

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age and again at around puberty. It is a catabolic disorder in which circulating insulin is virtually absent, plasma glucagon is elevated, and the pancreatic B cells fail to respond to all insulinogenic stimuli. Exogenous insulin is therefore required to reverse the catabolic state, prevent ketosis, reduce the hyperglucagonemia, and reduce blood glucose. DISEASES INVOLVING (SYSTEMIC DISEASES) MULTIPLE ORGANS

are no diagnostic blood tests. The erythrocyte sedimentation rate (ESR) is raised in the acute stage. Tests for rheumatoid factor and other autoantibodies are negative; 60% of patients are HLA-B27 positive. X-rays are of no value in the acute stage of the disease, though signs of sacroiliitis may appear with the development of ankylosing spondylitis. Aspirated synovial fluid is inflammatory in nature with a high polymorphonuclear leucocyte count; the fluid is sterile.

Systemic lupus erythematosus (SLE) rheumatoid arthritis (RA) and other collagen vascular diseases These disorders feature vasculitis and collagen degeneration, plus a variety of focal inflammatory lesions and the presence of autoantibodies against many different self antigens. For example, antibodies to deoxyribonucleic acid (DNA) are found in SLE and antibodies to IgG (rheumatoid factor) occur in rheumatoid arthritis. In Goodpastures syndrome, antibodies are formed against the basement membranes of the pulmonary alveoli and the renal glomeruli. In these diseases, complement is activated by the antigen-antibody complexes, and neutrophils are attracted to the site. Neutrophils release various enzymes and oxygen radicals that damage the tissues. Although, in most patients, the immune stimulus that initiates these disorders is unknown, typical cases have followed sensitization by and foreign proteins. Other diseases in this category include ankylosing spondylitis, which is very common in people carrying the HLA-B27 gene; polymyositis- dermatomyositis, sjogrens syndrome and Reiters syndrome.

Treatment of autoimmune diseases The conceptual basis for the treatment of autoimmune diseases is to reduce the patients immune response sufficiently to eliminate the symptoms. Corticosteroids, such as prednione, are the mainstay of treatment, to which antimetabolites (such as azathioprine and methotrexate) can be added. The latter are nucleoside analogues that inhibit DNA synthesis in the immune cells. Immunosuppressive therapy must be given cautiously because of the risk of opportunistic infections. Anti-inflammatory agents Nonsteroidal anti-inflammatory drugs have been used since 1800s when salicin extracted from willow bark (1828), sodium salicylate (1875) and aspirin (1899) were synthesized. A large numbers of these drugs, which either selectively or non-selectively inhibit the enzyme cyclo-oxygenase (a synthetic enzyme for pros-taglandins) are currently in use to treat inflammatory disease. Anti-malarial

Rheumatic fever (RF) Rheumatic fever (RF) is a febrile disease, affecting connective of the throat by group A beta haemolytic strptococci. Although RF is not a communicable disease, it results from a communicable disease (streptococcal pharyngitis). RF often leads to rheumatic heart disease (RHD) which is a crippling disease. The consequences of RHD include continuing damage to the heart; increasing disabilities, repeated hospitalization and premature death usually at the age of 35 years even earlier. RHD is one of the most readily preventable chronic diseases.

Anti-malarial drugs have been used for the treatment of SLEq and RA since early 1900s. The precise mechanism of action remains uncertain, but they have been shown to inhibit cytokine (IL-1 and IL-6) production in vitro. The anti-malarial pass freely through cell membranes at neutral PH, but in acidic environments such as endosomes, they become protonated and can no longer diffuse freely. Anticytokine agents The development of tumour necrosis factor- (TNF-) inhibitors in the 1990s ushered in a new era of therapy of autoimmune disease using biological capable of interfering with the interactions between cytokines and their receptors. Methotrexate Methotrexate is a folic acid analog used extensively for

Reiters syndrome This syndrome consists of the triad of a seronegative reactive arthritis, non specific urethritis and conjunctivitis. The male to female ratio is 20:1 and most cases occur in young adults. HLA-B27 is present in about 60% of cases. The diagnosis in these conditions is entirely clinical; there

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Table 2. Research study.

Plant/title Ginseng

Activity In one study, it has been evaluated that ginseng polysaccharide decreases the expression of TNF- and interferon-gamma (IFN-), and regulate the function of lymphocytes in enteric mucosal immune system in collagen-induced arthritis (CIA) rats. This study indicates that ginseng polysaccharide could be used in the treatment of autoimmune disease (Hongyan et al., 2011) It has been studied that aqueous extract of O. basilicum is a powerful natural immunomodulatory spice influencing various types of immune-responses and have potential health effects (Tsai1 et al., 2011). It has been studied that T. cordifolia has immunomodulatory properties, and is used for the treatment of jaundice, skin diseases, diabetes and anemia (Chopra et al., 1982). In one study, it has been evaluated that T. cordifolia improves the phagocytic and bactericidal activities in patients suffering from polymorphism in surgical jaundice (Thatte et al., 1989). In one study, effect of feeding T. cordifolia has been observed in broiler birds which were immunosuppressed with cyclophosphamide, and found a significant rise in antibody titer against ND virus with augmentation of inflammatory reaction to skin contact sensitivity test (Kolte et al., 2007). Rege et al. (1989) and Bishavi et al. (2002) have proved the hepatoprotective effect of T. cordifolia.

O. basilicum

T. cordifolia

W. somnifera

Ocimum sanctum
A. racemosus

Akram et al. (2010) studied the immunomodulant effect of W. somnifera. Modulates humoral immune response (Kujur, 2001; Krishnamohan et al., 1997; Kumar, 2003). Stimulates both humoral and cell mediated immune responses (Kuttan et al., 1992).

the treatment of RA.

Autologous hematopoietic stem cell transplantation (HSCT) Hematopoietic stem cells are the earliest progenitor cells of the immune system and give rise to B and Tlymphocytes as well as antigen-presenting cells (monocytes, macrophages and dendritic cells). The rationale for HSCT as a therapy for autoimmune disease is based on the concept that the peripheral expansion of auto-reactive T- and B-cell clones is central to the pathogenesis of autoimmunity. DISCUSSION An autoimmune disease occurs when the immune system fails to recognize the bodys own tissues as self and mounts an attack on them. Disorders include RA, juvenile (insulin-dependent) diabetes, thyroiditis and multiple sclerosis. Illnesses are divided into those that affect much system. Autoimmune diseases are mostly of unknown aetiology although genetic, hormonal, microbiological and environmental factors are known to be implicated in their manifestation and severity. Many herbal plant preparations are prescribed to strengthen host resistance (Thatte and Dahanukar, 1986) due to their immunomodulatory activities (Table 2). Bodys immune system protects from disease and infection (Damian et al., 2008). In an autoimmune disease, immune system attacks healthy cells in your body by mistake. Autoimmune diseases can affect many

Anti-T-lymphocyte therapy T-cells play a key role in the pathogenesis of type IV autoimmune reactions and also, they are critical for generating the T-cell dependent autoantibodies mediating type lll autoimmune diseases.

Anti-B-lymphocyte therapy Rituximab is a cytotoxic chimeric human- mouse monoclonal antibody with a high affinity for CD20, a panB-cell surface antigen. It was developed originally for the treatment of B-cell lymphomas. Intravenous immunoglobulin Intravenous immunoglobulin (IVIG) is a preparation of human immunoglobulin pooled from thousands of healthy individuals. It was originally developed for replacement therapy in humoral immunnodeficiency syndromes but has more recently become an important therapeutic modality in severe autoimmune disorders, such as thrombocytppenic purpura, autoimmune haemolytic anaemia (AIHA), neuroimmunological diseases such as Guillain-Barre syndrome, SLE, certain forms of vasculitis, and polymyositis dermatomyositis.

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parts of the body. These diseases tend to run in families. There are more than 80 types of autoimmune diseases, and some have similar symptoms (Xiao et al., 1997). Several studies have demonstrated the effects of herbal extracts on the immune system (Martino et al., 2010). Natural medicinal products have been traditionally used for the treatment of various complications in eastern countries, particularly China, India and Iran since the immemorial time (Ram et al., 2009). In a healthy body, circulating antibodies attack and destroy pathogenic invaders by means of humoral or cell-mediated immunity. In autoimmune disease, circ-lating antibodies seek attack and destroy self-antigens found in healthy tissue. Immunomodulator is a substance which stimulates or suppresses the components of immune system including both innate and adaptive im-mune responses (Agarwal and Singh, 1969). Tinospora cordifolia increases leukocyte count (Manjrekar et al., 1999). Ocimum sanctum has been reported to modulate humoral immune response by releasing mediators for hypersensitivity reactions (Kujur, 2001; Krishnamohan et al., 1997; Kumar, 2003). Withania somnifera exhibits immunomodulatory activities and is usually used for the treatment of gouty arthritis (Akram et al., 2010). A. racemosus stimulates both humoral and cell mediated immune responses in Swiss albino mice by Kuttan and Kuttan (1992). A. racemosus extracts increase phagocytic activities of macrophages in vitro (Rege and Dahanukar, 1993).

Conclusion Autoimmune diseases may be greatly improved by strengthening the immune system with nutritional supplements and by making healthy lifestyle changes in diet and stress reduction. The protocols needed may include prescription drugs as well as the following supplements. Extracts of several plants have shown impressive spectrum of biological activities as well as immunomodulatory effects (Martino et al., 2010).
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Hahn BH, Tsao BP (2008). Pathogenesis of systemic lupus erythematosus. In: Firestein GS, Budd RC, Harris ED Jr., et al., eds. Kelley's Textbook of Rheumatology. 8th ed. Philadelphia, Pa: Saunders Elsevier, Chap. 74. Hellar ED (1975). Resistance of maternal antibodies against Newcastle disease virus in chicks from immune parents and its effect on vaccination. Indian J. Comp. Microbiol. Immunol. Inf. Dis., 8(3): 106110. Hongyan Z, Wandong Z, Cheng X, Cheng L, Shaohua X (2011). effect of ginseng polysaccharide on TNF- and IFN- produced by enteric mucosal lymphocytes in collagen induced arthritic rats, JMPR, 5(9): 1536-1542 Kalita DN, Dutta GN (1999). Immunomodulatory effect of levamisole upon Newcastle disease, pigeon pox and Marks disease vaccination in broiler chicks. Indian Vet. J., 76: 490-492. Krishnamohan AV, Reddy DB, Sarma B, John KJ (1997). Studies on the effects of levamisole against Newcastle disease virus in chicken.Indian J. Comp. Microbiol. Immunol. Infict. Dis., 8: 1-6. Kujur RT (2001). Evaluation of certain immunomodulatory agents in countering immunosuppressive effects of vaccine strain of infectious bursal disease virus in chicks. M.V.Sc. thesis. Rajendra Agricultural Univ., Bihar, India. Kumar P (2003). Studies on comparative immunomodulatory effect of herbal preparation and Vitamin E-Se in comparison to Levamisole in broiler chicks. M.V.Sc. thesis. Birsa Agricultural Univ., Ranchi, India. Kuttan G, Kuttan R (1992). Immunomodulatory activity of a peptide isolated from Viscum album extract. Immunol. Invest., 21: 285-296. Manjrekar PN, Jolly CI, Narayan S (1999). Comparative studies of the immunomodulatory acivities of Tinospora cordifolia and Tinospora sinensis. Fitoterapia, 71: 254-257. Martino RF, Davicino RC, Mattar MA, Casali YA, Correa SG, Anesini C, Micalizzi B (2010). In vitro immunomodulatory effects of fractions obtained from aqueous extracts of Larrea divaricata Cav (Jarilla) on mouse peritoneal macrophages. Immunopharmacol. Immunotoxicol., 32(1): 125-132. Martino RF, Davicino RC, Mattar MA, Casali YA, Correa SG, Anesini C, Micalizzi B (2010). In vitro immunomodulatory effects of fractions obtained from aqueous extracts of Larrea divaricata Cav (Jarilla) on mouse peritoneal macrophages. Immunopharmacol. Immunotoxicol., 32(1): 125-132. Meroni PL, Schur PH (2010). ANA screening: an old test with new recommendations. Ann. Rheum. Dis., 69: 1420-1422. Ram A, Joseph DA, Balachandar S, Singh VP (2009). Medicinal plants from Siddha system of medicine useful for treating respiratory diseases. Int. J. Pharm., 1: 20-30. Rege NN, Dahanukar SA (1993). Quantitation of microbicidal activity of mononuclear phagocytes : an in vitro technique. J. Postgrad. Med., 39(1): 22-25. Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P, Khamashta MA(2010). Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann. Rheum. Dis., 69: 20-28. Segal JB, Powe NR (2006). Prevalence of immune thrombocytopenia: analyses of administrative data. J. Thromb. Haemost., 4(11): 23772383 Thatte UM, Dahanukar SA (1986). Ayurveda and contemporary scientific thought. Trends Pharmacol., Sci., 17: 248-257 Tsai KD, Lin BR, Perng DS, Wei JC (2011). Immunomodulatory effects of aqueous extract of Ocimum basilicum (Linn.) and some of its constituents on human immune cells, JMPR, 5(10): 1873-1883. Xiao BG, Link H (1997). Mucosal tolerance: A two-edged sword to prevent and treat autoimmune diseases. Clin. Immunol. Immunopathol., 85: 119-128.