Sjogren's Syndrome: Etiology and Definition

Sjögren’s Syndrome: Overview

• Sjögren’s (SHOW-gren) syndrome is an autoimmune disorder characterized by dry eyes and mouth, often accompanied by chronic arthritis.

Etiology & Definition

• The exact cause remains unknown, but genetic predisposition involving MHC haplotypes and environmental factors are implicated.
• MHC class II molecules (HLA-DQ, HLA-DR) may present self-antigens to CD4+ T-helper cells, causing immune dysfunction.
• Certain HLA haplotypes (like HLA-DR3) are more likely to misidentify self-antigens from exocrine glands.
• Unlike many other organs, salivary and lacrimal glands contain specialized epithelial cells that interact closely with immune cells.
• Environmental factors might trigger the immune dysfunction; Epstein-Barr Virus (EBV) is suspected in the disease's development.
• Viral infections (Epstein-Barr virus, cytomegalovirus, hepatitis C virus, and human T-lymphotropic virus-1) are linked to triggering autoimmune responses.
• Molecular mimicry and hormonal factors, such as estrogen, are also possible contributing factors.
• Estrogen may enhance immune response, increasing the risk of the autoimmune disease in women.

Epidemiology

• Affects 0.5%–1% of the population; about half of rheumatoid arthritis patients also have Sjögren’s.
• It can occur at any age but usually appears after 25 years, predominantly in middle-aged women (9:1 female-to-male ratio).
• There is no ethnic or geographic bias noted in incidence.

Pathogenesis

• The characteristic lesion is Focal Lymphocytic Sialadenitis (FLS) in exocrine glands.
• FLS lesions cause exocrine gland dysfunction, infiltration by mononuclear cells and production of autoantibodies and cytokines, reducing tear production.
• Dysfunctional exocrine glands cause skin dryness, tracheal irritation, and vasculitis as immune complexes deposit in the skin, joints, and organs.
• Antigen-presenting cells (APCs) activate T cells, which secrete pro-inflammatory cytokines.
• Cell damage releases DNA, RNA, and histones, picked up by APCs and presented to T cells.
• T cells inappropriately activate B cells to form anti-nuclear antibodies (ANAs).
• The main ANAs include anti-SSA (Ro) and anti-SSB (La).
• T cells and autoantibodies target exocrine glands, increasing inflammation and leading to fibrosis and loss of secretory function.

Types of Sjögren’s

• Primary Sjögren's syndrome (Sicca syndrome) occurs alone.
• Secondary Sjögren’s syndrome occurs with other autoimmune diseases like rheumatoid arthritis.

Clinical Presentation

• Dry eyes (Keratoconjunctivitis Sicca) due to lacrimal gland involvement causes blurred vision, itching, redness and burning.
• Dry mouth (Xerostomia) from salivary gland issues results in difficulty tasting, swallowing, and cracked mouth fissures.
• Respiratory issues include dryness in upper respiratory tract, causing ulceration, perforation of the nasal septum, crusting, and bleeding.
• Swollen glands can compress nearby structures, especially nerves causing pain.
• Other dryness issues include dry skin and vaginal dryness.
• There is an increased risk of infections, digestive problems, and joint and muscle pain.
• In some cases it presents with recurrent bronchitis and abnormal liver function.

Diagnosis

• Diagnosed by testing for decreased gland secretion via Sialometry to measure salivary flow.
• Blood tests can show the presence of anti-SSA and anti-SSB antibodies.
• A lip biopsy can confirm the presence of CD4+ T cells, plasma cells, and macrophages.

DiGeorge Syndrome: Overview

• Approximately 90% of cases are due to a deletion on chromosome 22q11.2, often called 22q11.2 deletion syndrome.
• Arises de novo and includes an absent or hypoplastic thymus, cardiac abnormalities, hypocalcemia, and parathyroid hypoplasia.

Etiology & Occurrence

• Identified by Dr. Antle de George in 1965.
• Characterized by microdeletion of 22q11.2 locus.

Epidemiology

• Occurs in approximately 1 in 4,000 to 6,000 live births.

Key Features

• Patients express phenotypes ranging from cardiac abnormalities and hypocalcemia to hypoplastic thymus.
• The most studied gene is TBX1, which leads to embryologic dysfunction.
• Failure in embryologic development of pharyngeal pouches leads to absence or hypoplasia of the thymus and parathyroid glands.
• Has a 30-fold increased risk of developing psychiatric pathologies.
• Diagnosis can occur prenatally, in pediatric periods, or in adulthood.

Genetic Basis

• TBX1 is involved in normal development of the pharyngeal pouches, specifically pouches three and four.
• The third pharyngeal pouch develops into the thymus and the inferior parathyroid gland.
• The fourth pouch develops into the superior thyroid gland.
• The 22q11.2 deletion results in underdeveloped thymus and parathyroid glands, causing hypoplasia.

Clinical Manifestations

• Partial DiGeorge syndrome causes mild to moderate thymic dysfunction.
• Congenital heart defects, particularly truncus arteriosus and tetralogy of Fallot, are fairly common.
• The deletion also leads to certain facial abnormalities like a cleft palate and a characteristic facies.

Consequences of Thymic Hypoplasia

• Causes a deficiency in mature T cells, leading to immunodeficiency.
• Complete DiGeorge syndrome is fatal within the first year due to a severely compromised immune system.

Consequences of Parathyroid Hypoplasia

• Decreased parathyroid hormone leads to low blood calcium levels, called hypocalcemia.

Diagnosis

• Genetic testing confirms the 22q11.2 deletion.
• Blood tests reveal T cell numbers, function, calcium, and parathyroid hormone levels.

Management

• Infections due to immunodeficiency are treated with antibiotics.
• Hypocalcemia is managed with vitamin D and calcium.

Treatment

• Involves immune support, calcium supplements, cardiac surgery, and psychiatric care.
• Thymus transplant is required for complete DiGeorge syndrome.
• Surgical repair is needed for heart defects.

Systemic Lupus Erythematosus (SLE): Overview

• SLE is a quintessential autoimmune disease with impaired clearance, upregulated immune responses, and immune complex and complement activation.
• Many organs and tissues are affected, which results in autoimmune patterns that change over time, complicating and delaying diagnosis.

Etiology & Epidemiology

• Affects women of childbearing age (15-44 years).
• Though present across ethnicities, it is more prevalent in people with African descent.
• Approximately 322,000 cases estimated in the U.S.
• The onset requires interaction between genetic predisposition, environmental precipitants, immune/humoral factors, and co-inflammatory stimuli.

Pathogenesis

• Involves defective clearance of apoptotic waste and immune complexes, along with neutrophil extracellular traps.
• Disrupts lymphocytes and interferon pathways.
• Genes such as HLA, STAT4, and BLK are associated with predisposition.
• Environmental triggers include smoking and infections with Epstein-Barr Virus (EBV).

Immunological Aspects

• T cells are defective (fail to produce IL-2), trending towards Th17 or T reg phenotypes, with an excess of double-negative T lymphocytes.
• Apoptotic cells (e.g., UV light-exposed keratinocytes) release blebs rich in autoantigens.
• Photosensitivity activates TLR 7/9, producing type one interferon and the classic butterfly rash.

Molecular Mechanisms

• Defective clearance of apoptotic cells leads to the release of cellular contents, triggering an immune response.
• Ineffective phagocytic cells or dysfunctional molecular machinery prevent proper recognition and removal of dead cells.
• Genetic predispositions and mutations disrupt immune functions, such as phagocytosis, complement activation, and cytokine regulation.
• HLA alleles alter the ability of antigen-presenting cells to process and present autoantigens or increase autoreactive T cell activation.

Neutrophil Extracellular Traps (NETs)

• Excessive NETs exacerbate inflammation in SLE.
• Overactive neutrophils release web-like structures composed of DNA, histones, and proteins that trap pathogens.
• NETs in SLE contain nuclear material that trigger immune responses against the body’s own tissues.

Environmental Triggers

• These include UV radiation, infections, smoking, and certain medications. Cigarette Smoking: Significantly contributes to SLE.
• UV light causes DNA damage.
• Epstein-Barr Virus (EBV) can trigger immune responses in individuals with a genetic predisposition.
• Certain medications induce drug-induced lupus.

Role of Sex Hormones

• Estrogen contributes to the higher incidence in women.

Clinical Manifestations

• The classic presentation is fever, joint pain, and rash in women of childbearing age.
• Symptoms can vary, affecting different organs and systems, making diagnosis difficult.
• Common symptoms include fever, weight loss, and organ-specific issues.

Disease Mechanisms

• Environmentally triggered cell damage releases nuclear antigens.
• Genetic components cause less efficient apoptotic body and nuclear antigen clearance.
• Immune cells recognize nuclear antigens as foreign, initiating an immune response.
• The inflammation causes most of the symptoms of lupus, a type III hypersensitivity reaction.

Diagnostics

• Anti-nuclear antibodies (ANAs) are present in almost all cases of lupus.
• Diagnosis is given only if four or more of 11 diagnostic criteria are met.

Omenn Syndrome: Overview

• Omenn syndrome is an autosomal recessive inherited syndrome in which both parents are carriers for the mutation but are typically asymptomatic.
• It is a type of severe combined immunodeficiency disease (SCID) where both cell-mediated immunity and antibody protection are impacted.
• First characterized in 1965 by G. Omen.

Epidemiology

• SCID as a whole affects one in 75,000 to 100,000 newborns, but the exact prevalence of Omen syndrome is unknown.

Pathogenesis

• Typically presents during the first year of life, with features of SCID, including erythroderma, lymphadenopathy, and hepatosplenomegaly.
• Protein loss may lead to metabolic disturbances.
• Causes leaky SCID in genetic mutations in RAG1 and RAG2, due to partial enzymatic activity.
• The restrictive V(D)J recombination permits limited TNB cell development, directed towards self-antigens, leading to autoimmunity.
• Infants around three months of age will have severe immune deficiencies.

Genetic Mechanisms

• Both cell-mediated immunity and antibody protection is affected.
• Individuals have virtually no immune protection and are prone to resist infections with the potential to be life threatening.
• Classified as T plus B minus, individuals do have malfunctioning T cells but virtually no B cells.
• Most cases are attributed to mutations of the RAG genes, which provide instructions for proteins active in B and T lymphocytes.
• When mutated, the B and T cells are limited in helping recognize invaders.
• Normal numbers of T cells can lead to abnormal attack own cells, with genetic hetero.

Clinical Presentation

• Features distinct symptoms include erythroderma and alopecia. Infections: Infections are common, contracting viral, bacterial, and fungal infections.
• Individuals will experience with autoimmune issues. Distinctive Signs and Symptoms: Swollen Lymph Nodes: Lymphadenopathy, or enlarged lymph nodes. Enlarged Liver/Spleen: Hepatomegaly and splenomegaly or enlarged liver and spleen. Immunoglobulin Levels: Reduced IgG, IgA, and IgM: Low levels of IgG, IgA, and IgM. Elevated IgE: High levels of IgE.

HIV/AIDS: Overview

• The virus infects CD4 positive T helper cells/ The virus leads to autoimmune Deficiency Syndrome. was officially identified in 1983.
• Considere to be zoonotic disease
• Was first transmitted from Chimpanzee to W Africa:
• Was MutliFactorial-Originated From West Africa
• The virus spread through migration, travel, sexual, practice drug use and war
• Incidence of HIV has remained generally stable by ~50,000 new infections/year.
• HIV/Ais is not always in the full state of AIDS.

Etiology

• Officially identified in 1983, HIV is considered a zoonotic disease.
• A subspecies of chimpanzee native to West Africa was the original source.
• Transmission of HIV is multi-factorial, originating from West Africa and spreading via migration, travel, sexual practices, drug use, and war.

Epidemiology

• An estimated 1.2 million people in the United States, aged 13 and older, are living with HIV infection.

Key Stages of Infection:

• Primary Stage; Acute, the virus is highly infection, not Detectable
• Window Period, 2-14 wks the Generation of Antibodies-Seroconversion w/ positive Test
• Asymptomatic Stage: often called Clinical Latency
• Symptomatic: clinical manifestation appears. clinical manifestations

Pathogenesis

• Enters the BloodStream-> Infects CD4 cells: Positive T-Lymphocytes
• Destroying CD4 Cells leads to damaging adaptive, Cytotoxic & Humoral Immune Responses
• HIV- In the Pathogeneses can beAsymptomatic
• Occurs After weeks and years: Nausea, cold symptoms, Malaise,Weight Loss General Infections
• Unforuantley Patients do not Recognize the Uniqueness of the Symptoms of Infection (not unique to HIV

Symptoms and Features:

• HIV Infection, Patients do not Recognize the Uniqueness of the Symptoms to Infection of of HIV/AIDS
• An AIDS Diagnosis
• CD4 Count is less thant 200 compared to thw 1,000 normal range

Transmission Routes

• Unprotected Anal Vaginal Oral Sex and Through Needle Exchange
• Virus can Pass Through from Mom -> Baby During Pregnancy, Breastfeeding & Birth

Pathogenesis cont…

• HIV is a Retrovirus in Single Stranded POSTIVE Sense
• RETRO part is Not Referring Retro Style
• The enzyme use: Reverse Transcriptase -> transcribe a Double Stranded(Complementary Piece of Provisional DNA
• ** Provisional** = Ready to Integrate Into Host CNA (sneaky sneaky -When the Immune CELLs -> activated ->They Start Transcribing -> Translating the proteins needed for immune response ( ironically

Viral Trophism

• The Virus can Mutate when is Replicates

Phases of Infection:

• 1. Acute Phase: HIV the ENTERS the BODY THOUGH SEX- ( R5 Strain binds to CCR binds- Macrophages, T-Cells Dendritic cells

• R5 - Dendritic Cells -> capture &migrate in the epithelial Tissue & Mucosal TIssue -> and the HIV Field Day Infecting: Macrophage, Tcells and Dendritic

• 2. Chronis/Cllinly Latent Phase 2-10 Years the Amount of CD4 Cells are DECLINING While HIv is Increasing->

• In the Stage Patients are devloping X^

• Targets CD4 -> Destore Cd4 -> this takes place due to the Lymphoid Tissue And the T Cells are dropping Between 200 Cells and 100 Cell Patients Start-> Swollen Lymph nodes-> Orol Haria Lipolaka, Oral Candidas- yeast the infection of in Mouth