Defining autoimmune diseases
Autoimmune diseases are direct consequences of immune-mediated inflammatory reaction with some features of chronic inflammation.
In organ-specific autoimmune diseases, the immune response is against a single organ. During systemic autoimmune diseases, there is a wide-spread immune response aginst an antigen.
Autoimmune diseases and immunological tolerance
In order for our tissues to live in harmony with our immune cells, there must be an immunological tolerance against self-antigen. Examples of immunological tolerance are central and peripheral tolerance.
Central tolerance occurs in primary lymphoid organs. In the thymus, immature CD8+ T lymphocytes that react to self-antigen die by apoptosis in negative selection. CD4+ T lymphocytes that react against self-antigen transform into regulatory T lymphocytes.
Developing B lymphocytes in the bone marrow undergo receptor editing in case of reaction against self-antigen.
Peripheral tolerance occurs in the circulation, & lymphoid tissues. Regulatory T cells formed in thymus suppress autoreactive T & B lymphocytes found in peripheral tissues . Regulatory T cell secretes IL-10 which inhibits lymphocytes activation.
Types of autoimmune diseases
The types of autoimmune diseases are: SLE; rheumatoid arthritis; sjogren syndrome; systemic sclerosis; inflammatory myopathies; mixed connective tissue disease; polyarteritis nodosa with vasculitides.
Systemic Lupus Erythematosus (SLE)
Systemic lupus erythematosus: A systemic autoimmune disease due to formation of immune complex deposit in blood vessels, and tissues. In this disease, anti-nuclear antibodies (ANAs) attack nuclear antigens. Antibodies to DNA and Smith (Sm) antigen are diagnostic of SLE.
Causes of SLE include: DNA alteration; autoreactive B lymphocyte release; B cell activation by Toll-like receptors. Sunlight exposure; sex hormone & drugs such as D-penicillamine; hydralazine, procainamide worsen SLE.
The clinical manifestations are: fever; butterfly rash over the face; peripheral joint pain (arthritis); lymph node enlargement; pericarditis; pleuritis; lupus nephritis; anemia; thrombocytopenia; leukopenia; fever; weight loss; renal failure.
The subtypes of SLE are chronic discoid lupus erythematosus, subacute cutaneous lupus erythematosus & drug-induced lupus erythematosus.
Chronic discoid lupus erythematosus mainly affects the skin of face and scalp. It manifests as an elevated erythematous swollen skin, with scaly plaques. It is positive for ANAs
The subacute cutaneous lupus erythematosus is a widespread superficial non-scarring skin rash, positive for antibodies to SS-A antigen. SS-A is a ribonuclear protein antigen. Individuals with HLA-DR3 are susceptible to this disease.
Drug induced lupus erythematosus is causes by D-penicillamine, hydralazine, procainamide & isoniazid. It is positive for antibodies to histone proteins, and manifests as fever, joint pain, fever, serositis.
Rheumatoid arthritis
This is a systemic autoimmune disease, mediated by T cells that primarily affects joints. It may affect other organs such as skin, heart, lung, and blood vessels.
Sjogren/ Sicca syndrome
This is a systemic autoimmune disease, mediated by T helper lymphocytes, that destroys lacrimal and salivary glands. There is also the presence of B cells, plasma cells and antibodies. Antibodies to SS-A (Ro) & SS-B (La) antigens are diagnostic markers for Sjogren syndrome.
Clinical manifestations include: dry mouth (xerostomia); dry eye (keratoconjunctivitis); blurry vision; itchy and burning eyes; difficulty swallowing; cracks in the mouth.
Systemic sclerosis/Scleroderma
A systemic autoimmune disorder, mediated by T cells, that results is fibrosis of skin, lungs, G.I tract, heart, muscle, kidney. Diffuse scleroderma affects a wide area of skin with progressive visceral damage. Limited scleroderma affects manly fingers, forearm, and face. Antibody to DNA topoisomerase 1 antigen (anti Scl-70).
Patients with limited scleroderma may have CREST syndrome. Calcinosis, Raynaud’s phenomenon, Esophageal dysmotility, Sclerodactyly & Telangiectasia.
Clinical manifestations include: skin thickening, episodic vasoconstriction of arteries & arterioles; dysphagia; intestinal obstruction and malabsorption; anemia; pulmonary fibrosis, malignant hypertension with renal failure; cardiac failure.
Inflammatory myopathies
They affect skeletal muscles, and may occur secondary to systemic sclerosis. They include: dermatomyositis, polymyositis, & inclusion-body myositis.
Mixed Connective tissue disease
This is an immune-mediated disorder, with a combination of presentations from systemic sclerosis, polymyositis, and SLE. It is positive for antibodies to U1 small nuclear Ribonucleoprotein (U1 snRNP). This disorder leads to pulmonary hypertension, and renal disease.
Polyarteritis nodosa with vasculitides
Polyarteritis nodosa belongs to a group of disorders affected by necrotizing inflammation of blood vessel wall. This is an immune complex response that may affect any kind of blood vessels.
Rejection of tissue transplant
Tissue rejection occurs by direct recognition of donor MHC molecule by T lymphocytes. Here, donor’s MHC molecules mimick foreign peptides which triggers attack.
Rejection may also occur indirectly when the host’s MHC molecule presents peptides derived from donor organ to CD4+ T lymphocytes.
Other than T lymphocytes, antibodies take part in humoral rejection. This may take two forms: Hyperacute and acute humoral rejection. Hyperacute humoral rejection occurs to patients with preformed antibodies. Acute humoral rejection occurs to patients receiving graft transplant for the first time. A previously rejected kidney transplant produces preformed antibodies in hyperacute humoral rejection.
Rejection reaction is classified as hyperacute, acute, and chronic rejection. Hyperacute rejection starts in minutes to hours following organ transplant. Acute cellular or humoral rejection occurs in days, months or even years following organ transplant. In chronic rejection, there is progressive organ failure over few months.
In a hyperacutely rejecting kidney, there is few drops of bloody urine. Vasculitis is a sign of acute humoral rejection of kidney transplant.. Chronic cellular rejection of kidney transplant shows mononuclear infiltration with interstitial hemorrhage. Chronic rejection of kidney transplant reveals raised creatinine, and renal fibrosis.
Problems in bone marrow transplant surgery
Two common problems arise from bone marrow transplant surgery, which are: graft-versus-host (GVH) disease and immunodeficiency. GVH arises when donor’s immune T lymphocytes attack host’s HLA antigens. Immunodeficiency occurs following removal of T cells from donor’s bone marrow, & attack on host immune cells by grafted T cells. Clinical manifestations of GVH disease are: Skin rash, bloody diarrhea, cholestatic jaundice, esophageal stricture.
Immunodeficiency syndromes
There are primary and secondary immunodeficiency disorders. Primary immunodeficiency disorders are due to genetic abnormalities that affects adaptive immunity, leading to defective innate immunity. They include: X-linked agammaglobulinemia; common variable immunodeficiency; isolated IgA deficiency; hyper IgM syndrome; DiGeorge syndrome; SCID; Wiskott-Aldrich syndrome; genetic deficiency of complement system.
X-linked agammaglobulinemia (Bruton’s Agammaglobulinemia):
This is a failure of developing B cells (pro- B cells, pre-B cells) to mature, due to mutation of Bruton tyrosine kinase. It mainly affects male with symptoms appearing until 6 months of age.
Clinical manifestation include: bacterial respiratory tract infections, encephalitis, poliomyelitis. Microbes that cause these manifestations are streptococcus pneumonia, staphylococcus aureus, H. influenzae, poliovirus, echovirus, and coxsackievirus.
Common variable immunodeficiency:
Occurs due to inability of mature B cells to differentiate into plasma cells leading to antibody deficiency. Problem is due to BAFF receptor mutation, necessary for B cell activation and differentiation into plasma cell. Symptoms appear in adolescence.
Clinical manifestation include: diarrhea, recurrent respiratory tract infection, hypogammaglobulinemia, meningoencephalitis, risk of gastric cancer, lymphoid malignancy.
Isolated IgA deficiency:
This is failure of B cells to produce IgA leading to its deficiency. Less common among blacks and Asians. Manifestations include urinary, respiratory tract infection & diarrhea. There is also a mutation in BaFF receptor.
Hyper IgM syndrome:
In this disorder, there is high level of IgM, absent IgA, IgE, with very low IgG. Disorder is due to mutation in gene for CD40 ligand located on Xq26.
Clinical manifestations include: hemolytic anemia, thrombocytopenia, neutropenia, pneumocystis pneumonia.
DiGeorge syndrome:
This is a T cell deficiency resulting from the failure of the development of thymus and parathyroid gland. Included are abnormal structure of mouth, ear, face and defect of the heart and great vessels. It is a non-familial disorder that causes recurrent microbial infection.
Severe Combined Immunodeficiency (SCID):
A familial disorder with a characteristic defect in both humoral and cell-mediated immune response. It usually affects infants. Patients are prone to infections like: Candida albicans, P. jiroveci, Pseudomonas, cytomegalovirus, varicella.
Clinical manifestations include diaper rash, morbilliform rash, death in the first year without bone marrow transplant.
Wiskott-Aldrich syndrome:
This is an X-linked recessive disorder with a feature of immunodeficiency, eczema and thrombocytopenia. Patients have very low IgM, normal IgG, with high levels of IgA and IgE. Caused by mutation in gene for Wiskott-Aldrich syndrome protein on Xp11.23. Risk of non-Hodgkin B-cell lymphoma is high.
Genetic deficiency of complement system:
C2 deficiency results in SLE- like autoimmune diseases; C3 deficiency results in recurrent pyogenic bacterial infections; C5-C9 deficiency leads to recurrent Neisseria meningitidis and Neisseria gonorrheal infections.
Autosomal dominant C1inhibitor deficiency leads to hereditary angioedema. Clinical presentation include: episodes suffocation, nausea, vomiting, diarrhea.
Secondary immunodeficiency disorders
Secondary immunodeficiency disorders arise from infections, cancer, irradiation, chemotherapy, poor nutrition.
Acquired Immunodeficiency Syndrome (AIDS)
This is among the secondary causes of immunodeficiency. It occurs due to Human Immunodeficiency Virus (HIV) infection. Routes of transmission include parenteral inoculation, sexual contact, transmission from mother to newborn.
HIV infection targets CD4+ cells, and the central nervous system. Viral budding causes death and loss of CD4+ lymphocytes which is the genesis of AIDs. Phases of clinical manifestation include: acute retroviral syndrome, chronic phase, & clinical AIDs.
Acute retroviral syndrome begins 3 to 6 weeks after exposure, and resolves in 2 to 4 weeks. It manifests as flulike symptoms including fever, myalgia, sore throat, weight loss, fatigue, rash, cervical lymphadenopathy, vomiting, diarrhea.
In chronic phase, patients are asymptomatic or present with few opportunistic infections. These infections may include oral candidiasis, vaginal candidiasis, herpes zoster, mycobacterium tuberculosis.
AIDs develop 7 to 10 years following infection. Presents with fever lasting >1 month; diarrhea, fatigue, weight loss, candidiasis severe opportunistic infections, encephalopathy. secondary neoplasms.
Opportunistic infections in HIV/AIDs are: P. jiroveci; Candida; Histoplasma capsulatum; Cryptococcus neoformans; Salmonella; Shigella; mycobacterium tuberculosis, mycobacterium avium complex, cytomegalovirus; varicella-zoster virus; herpes simplex virus; papovaviruses; Toxoplasma gondii; Cryptosporidium;
Neoplasms in AIDs occur due to reactivation of oncogenic viruses. Kaposi sarcoma herpesvirus which causes Kaposi sarcoma; EBV which causes B-cell lymphoma; human papillomavirus which causes cervical and anal cancer.