The immune system uses several mechanisms to damage the tissues and organs of the patient during an autoimmune disease. These mechanisms are classically distinguished into T cell-mediated and antibody-mediated.

T Cell-Mediated Damage

In many autoimmune diseases, lymphocytes infiltrate the anatomical site that contains the autoantigen(s) they recognize, and form structures similar to those found in lymph nodes. These abnormal structures are called “tertiary lymphoid structures” and are the pathological hallmark of tissue autoimmunity. They form in organs that normally do not participate to immune functions and do not have lymphocytes, such as the synovial membrane of the joints, the heart, the thyroid, the brain, or the salivary glands. Although they lack a capsule and the complex architecture seen in lymph nodes, tertiary lymphoid structure mimic the way lymphocytes assemble in lymph nodes, with B cells located in the center and T cells in the periphery.

Tertiary Lymphoid Structures

The structure of a normal lymph node is shown here to the right. You can see a highly cellular outer part, called cortex, and a less cellular inner part, called medulla. The cortex contains many dense cellular aggregates composed predominantly of B cells. These aggregates, called lymphoid follicles, often show a dark stained rim (mantle), composed of resting B cells, and a light-stained center (germinal center), composed of actively proliferating B cells. They are both B cells both the ones in the center are paler because their nuclear chromatin is more open and loosely packed. Around and underneath the B-cell follicles are the T cells, which populate the majority of the deeper cortex.

During autoimmune diseases, structures similar to the ones found in normal lymph nodes develop in the organ targeted by the autoimmune attack.

An example: Tertiary Lymphoid Structures in the Thyroid Gland

One of the most common autoimmune disease in humans is Hashimoto thyroiditis, an organ-specific disease that affects the thyroid gland. It was first described in Japan in 1912 by Dr. Hashimoto, then remained poorly reported for a few decades, and gradually acquired widespread recognition and highest prevalence. The first case at the Johns Hopkins Hospital of what we would call nowadays Hashimoto thyroiditis was this case 43,751 from July 30, 1928. A photo of the original glass slides is shown here.

  • Hashimoto Thyroid

    Hashimoto thyroiditis

    If we look at those 1928 slides under the microscope we see that the thyroid gland is remarkably infiltrated by lymphocytes. Lymphocytes form typical tertiary lymphoid structures with clearly visible germinal centers.

  • T cells

    T cells

    If we stain a Hashimoto thyroiditis thyroid gland using a T cell marker, we see the characteristic distribution of T cells around the lymphoid follicles.

  • B Cells

    B cells

    If we stain a Hashimoto thyroiditis thyroid gland using a B cell marker, we see the characteristic distribution of B cells inside the lymphoid follicles.

Hashimoto thyroiditis

If we look at those 1928 slides under the microscope we see that the thyroid gland is remarkably infiltrated by lymphocytes. Lymphocytes form typical tertiary lymphoid structures with clearly visible germinal centers.


T cells

If we stain a Hashimoto thyroiditis thyroid gland using a T cell marker, we see the characteristic distribution of T cells around the lymphoid follicles.


B cells

If we stain a Hashimoto thyroiditis thyroid gland using a B cell marker, we see the characteristic distribution of B cells inside the lymphoid follicles.


Tertiary lymphoid structures are a site where autoreactive lymphocytes proliferate and mature. Here, B cells undergo affinity maturation, meaning they become strong producers of autoantibodiesthat have high affinity autoantibodies. And T cells develop into specialized effector cells (CD8 T cells and the various subset of CD4 T cells). Mature CD8 T cells can directly kill the target cells that express the antigen they recognize. This effector mechanism, called cytotoxicity, occurs predominantly via membrane-bound molecules, such as Fas ligand and granzyme B. Mature CD4 T cells mediate their damage by differentiating into various subsets that release high levels of a particular cytokine. For example, the T helper 1 subset (Th1) releases mainly IFN gamma and TNF alpha; the Th9 subset releases mainly IL-9; and the Th17 subset releases mainly IL17A. The cytokines in turn damage the target cell and recruit other inflammatory cells to perpetuate and escalate the inflammatory process. The importance of the pathological role of cytokines is shown by the success treatments aimed at blocking cytokine action have in patients with autoimmune diseases.

In the end, the target organ infiltrated by lymphocytes is damaged or completely destroyed and clinical disease ensues.

Antibody-Mediated Damage

ANTIBODY-MEDIATED DAMAGE

There are some autoimmune diseases where antibodies play the major role in causing the clinical symptoms autoimmune patients have. Some examples of antibody-mediated autoimmune diseases are:

We know that antibodies are the culprit because these autoimmune diseases can be transferred from an affected patient to a normal individual by the transfer of patient-derived serum (or immunoglobulins), and from the transfer of the disease from the affected mother to her baby in the neonatal period. T cells are still critical in these diseases. In fact, the affinity maturation of the B cells producing antibodies requires the help from CD4 T cells. So, one could say that CD4 T cells are the initial drivers of the pathogenesis in antibody-mediated diseases, But the fact remains that in these conditions antibodies by themselves are pathogenic, that is they can cause the symptoms.

In antibody-mediated autoimmune diseases the infiltration of the target organ with lymphocytes is more difficult to demonstrate. For example, in myasthenia gravis the target organ is the neuromuscular junction, the end plate found throughout skeletal muscles. This structure contains the main autoantigens targeted in myasthenia gravis: the acetylcholine receptor and the muscle-specific tyrosine kinase. Although T and B lymphocytes have been observed at the neuromuscular junction, they are rare and found only in a subset of patients. In myasthenia gravis, the B cells producing autoantibodies against the acetylcholine receptor are located mainly in the thymus, and organ made up predominantly of developing T cells. And, in fact, surgical removal of the thymus has long been used as a treatment for patients with myasthenia gravis. Acetylcholine receptor antibodies do fall after thymectomy but do not disappear, indicating there are other anatomical locations containing the autoantibody-producing B cells. In other examples, the target of the autoimmune attack is a movable part, such as the platelets in the blood circulation, and therefore there cannot be the pathological hallmark of autoimmune diseases.

Autoantibodies can directly cause pathological damage by a variety of mechanisms that involve either binding of the antibody to a cell-associated antigen or binding to a soluble antigen with the subsequent formation of immune complexes that then deposit in the affected tissues. Here are some examples of antibody-induced pathology.

Blockade of a cell surface receptor   ▼

In myasthenia gravis, binding of the autoantibodies to the acetylcholine receptor disrupts receptor signaling, with resulting impairment of the neuromuscular transmission and muscle weakness. These antibodies can also attract complement to the end plate and cause muscle damage via the complement cascade. In the NMDA receptor encephalitis, autoantibodies bind to a subunit of the N-methyl-D-aspartate (NMDA) receptor, interfering with synaptic function and disrupting networking functions in the central nervous system.

Stimulation of a cell surface receptor   ▼

In Graves disease, autoantibodies bind to the thyroid stimulating hormone (TSH) receptor and constantly stimulate it. This protracted stimulation bypasses the normal negative feedback that thyroid hormones have on the pituitary hormone TSH, and therefore the thyroid gland produces high levels of thyroid hormones, which cause the classical symptoms of hyperthyroidism.

Cell Death   ▼

In immune thromobocytopenic purpura or autoimmune hemolytic anemia antibodies bind to platelets or red cells and cause cell death. Death of the target cells occur because antibodies recruit components of the complement system, or because they attack natural killer cells that then mediate the cytotoxicity, or because the tail of the antibody, called crystallizable fragment or Fc, is recognized by phagocytic cells such as macrophages who then engulf and destroy the antibody-target cell complexes.

Disruption of cell-to-cell adhesion   ▼

Desmogleins are transmembrane glycoproteins that mediate cell-to-cell adhesion in the epidermis and mucous membranes. Patient with pemphigus vulgaris or foliaceous have antibodies against desmogleins. These antibodies interfere with the function of desmogleins so that cells come apart, giving rise to the characteristic blisters observed on the skin and oral mucosa. These antibodies can occupy region of the desmogleins that are important for adhesion (so called steric hindrance) and also induce clustering and endocytosis of the desmogleins, depleting therefore from the cell surface.

In several other autoimmune diseases such as rheumatoid arthritis and vasculitis, autoantibodies, although not capable on their own to transfer the disease, strongly contribute to the pathological damage.